Patent Publication Number: US-2023159930-A1

Title: Double stranded rna targeting angiopoietin-like 3 (angptl-3) and methods of use thereof

Description:
RELATED APPLICATIONS 
     This application claims priority to, and the benefit of, U.S. Provisional Application No. 63/281,253, filed Nov. 19, 2021. The contents of this application are incorporated herein by reference in their entirety. 
    
    
     INCORPORATION BY REFERENCE OF SEQUENCE LISTING 
     The Sequence Listing XML associated with this application is provided electronically in XML file format and is hereby incorporated by reference into the specification. The name of the XML file containing the Sequence Listing XML is “SANB-008_001US_SeqList_ST26”. The XML file is 561,421 bytes in size, created on Nov. 17, 2022. 
     BACKGROUND 
     Angiopoietin-like 3 (ANGPTL3) is a member of the angiopoietin-like family of secreted factors that regulates lipid metabolism and that is predominantly expressed in the liver. ANGPTL3 dually inhibits the catalytic activities of lipoprotein lipase (LPL), which catalyzes the hydrolysis of triglycerides (TG), and of endothelial lipase (EL), which hydrolyzes high density lipoprotein (HDL) phospholipids. In addition, ANGPTL3 regulates plasma triglyceride (TRG) levels due to its inhibitory action on the activity of lipoprotein lipase (LPL), and genetic variants of ANGPTL-3 are associated with hypertriglyceridemia. 
     In some animal models of obesity, reduction in ANGPTL3 expression has a protective effect against hyperlipidemia and atherosclerosis by promoting the clearance of TG, and has been shown to also lead to a decrease in cholesterol and LDL levels in animal models. Mice deficient in ANGPTL3 have very low plasma TG and cholesterol levels, while overexpression produces the opposite effects. In humans, the plasma concentrations of ANGPTL3 correlate positively with plasma HDL cholesterol and HDL phospholipid levels. The observed effects of ANGPTL3 on lipid metabolism make it an attractive target for therapeutic intervention. Accordingly, there is an unmet need for highly potent and tolerable compounds to inhibit ANGPTL3. The present application discloses novel, highly potent inhibitors of ANGPTL3 expression and their use in treatment. 
     SUMMARY 
     The present disclosure provides an isolated oligonucleotide comprising a sense strand and an anti-sense strand, wherein the sense strand comprises a nucleotide sequence that is substantially identical to a region comprising 19-25 nucleotides between any one of the nucleotide positions selected from: a) 52 to 93; b) 133 to 184; c) 246 to 304; d) 337 to 414; e) 433 to 503; f) 522 to 571; g) 617 to 700; h) 717 to 737; i) 836 to 905; j) 944 to 964; k) 1013 to 1093; l) 1353 to 1386; and m) 1407 to 1427, from the 5′ end of an Angiopoietin-like protein 3 (ANGPTL-3) mRNA sequence according to SEQ ID NO: 1, and the anti-sense strand is substantially complementary to the sense strand such that the sense strand and the anti-sense strand together form a double stranded region. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% identical to a region comprising 19-25 nucleotides between any one of the nucleotide positions selected from: a) 52 to 93; b) 133 to 184; c) 246 to 304; d) 337 to 414; e) 433 to 503; f) 522 to 571; g) 617 to 700; h) 717 to 737; i) 836 to 905; j) 944 to 964; k) 1013 to 1093; l) 1353 to 1386; and m) 1407 to 1427, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is identical to a region comprising 19-25 nucleotides between any one of the nucleotide positions selected from: a) 52 to 93; b) 133 to 184; c) 246 to 304; d) 337 to 414; e) 433 to 503; f) 522 to 571; g) 617 to 700; h) 717 to 737; i) 836 to 905; j) 944 to 964; k) 1013 to 1093; l) 1353 to 1386; and m) 1407 to 1427, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is substantially identical to a region between any one of the nucleotide positions selected from: a) 523 to 543; b) 680 to 700; and c) 1058 to 1078, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% identical to a region between any one of the nucleotide positions selected from: a) 523 to 543; b) 680 to 700; and c) 1058 to 1078, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is identical to a region between any one of the nucleotide positions selected from: a) 523 to 543; b) 680 to 700; and c) 1058 to 1078, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is substantially identical to a region between any one of the nucleotide positions selected from: a) 52 to 93; b) 133 to 184; c) 275 to 304; d) 342 to 377; e) 453 to 503; f) 548 to 571; g) 673 to 699; h) 717 to 737; i) 836 to 905; j) 944 to 964; k) 1013 to 1093; and l) 1353 to 1427, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% identical to a region between any one of the nucleotide positions selected from: a) 52 to 93; b) 133 to 184; c) 275 to 304; d) 342 to 377; e) 453 to 503; f) 548 to 571; g) 673 to 699; h) 717 to 737; i) 836 to 905; j) 944 to 964; k) 1013 to 1093; and l) 1353 to 1427, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is identical to a region between any one of the nucleotide positions selected from: a) 52 to 93; b) 133 to 184; c) 275 to 304; d) 342 to 377; e) 453 to 503; f) 548 to 571; g) 673 to 699; h) 717 to 737; i) 836 to 905; j) 944 to 964; k) 1013 to 1093; and l) 1353 to 1427, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a sequence that substantially identical to a region between any one of the nucleotide positions selected from: a) 54 to 74; b) 148 to 179; c) 246 to 282; d) 337 to 414; e) 433 to 495; and f) 522 to 542; g) 617 to 637; h) 838 to 858; and i) 1361 to 1381, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a sequence that is at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% identical to a region between any one of the nucleotide positions selected from: a) 54 to 74; b) 148 to 179; c) 246 to 282; d) 337 to 414; e) 433 to 495; and f) 522 to 542; g) 617 to 637; h) 838 to 858; and i) 1361 to 1381, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a sequence that is identical to a region between any one of the nucleotide positions selected from: a) 54 to 74; b) 148 to 179; c) 246 to 282; d) 337 to 414; e) 433 to 495; and f) 522 to 542; g) 617 to 637; h) 838 to 858; and i) 1361 to 1381, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the isolated oligonucleotide is capable of inducing degradation of the ANGPTL-3 mRNA. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand is a single stranded RNA molecule. In some embodiments of the isolated oligonucleotide of the present disclosure, the anti-sense strand is a single stranded RNA molecule. In some embodiments of the isolated oligonucleotide of the present disclosure, both the sense strand and the anti-sense strand are single stranded RNA molecules. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the single stranded RNA molecule of the sense strand comprises a 3′ overhang. In some embodiments, in the single stranded RNA molecule of the sense strand, the 3′ overhang comprise at least one nucleotide. In some embodiments, in the single stranded RNA molecule of the sense strand, the 3′ overhang comprise two nucleotides. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the single stranded RNA molecule of the anti-sense strand comprises a 3′ overhang. In some embodiments, in the single stranded RNA molecule of the anti-sense strand, the 3′ overhang comprise at least one nucleotide. In some embodiments, in the single stranded RNA molecule of the anti-sense strand, the 3′ overhang comprise two nucleotides. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the 3′ overhang comprises any one of thymidine-thymidine (dTdT), Adenine-Adenine (AA), Cysteine-Cysteine (CC), Guanine-Guanine (GG) or Uracil-Uracil (UU). 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises an RNA sequence of at least 20 nucleotides in length. In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises an RNA sequence of 20 nucleotides in length. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the anti-sense strand comprises an RNA sequence of at least 22 nucleotides in length. In some embodiments of the isolated oligonucleotide of the present disclosure, the anti-sense strand comprises an RNA sequence of 22 nucleotides in length. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the double stranded region is between 19 and 21 nucleotides in length. In some embodiments of the isolated oligonucleotide of the present disclosure, the double stranded region is 20 nucleotides in length. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the double stranded region comprises an anti-sense strand and a sense strand, according to any one of the pairs of anti-sense strand and sense strand sequences in Table 1, as described in the detailed description. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the anti-sense strand comprises a nucleotide sequence according to any one of: SEQ ID NOs: 2-62 and 200. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence according to any one of: SEQ ID NOs: 63-123 and 235. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the anti-sense strand comprises a nucleotide sequence according to any one of: SEQ ID NOs: 2-62 and 200; and the sense strand comprises a nucleotide sequence according to any one of: SEQ ID NOs: 63-123 and 235, wherein the anti-sense strand and the sense strand sequences have sufficient complementarity to allow formation of a double stranded region between the anti-sense and the sense strand. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, wherein the sense strand comprises a nucleotide sequence that is identical to a region between any one of the nucleotide positions selected from: a) 523 to 543; b) 680 to 700; and c) 1058 to 1078, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1, the double stranded region comprises: i) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 7 (5′ UUUUUAAGUGAAGUUACUUCUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 68 (5′ GAAGUAACUUCACUUAAAAA 3′); ii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 8 (5′ UGAAGAUAGAGAAAUUUCUGUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 69 (5′ CAGAAAUUUCUCUAUCUUCA 3′); or iii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 10 (5′ UUAAUGUUUGUUGUCUUUCCAG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 71 (5′ GGAAAGACAACAAACAUUAA 3′). 
     In some embodiments of the isolated oligonucleotide of the present disclosure, wherein the sense strand comprises a nucleotide sequence that is identical to a region between any one of the nucleotide positions selected from: a) 52 to 93; b) 133 to 184; c) 275 to 304; d) 342 to 377; e) 453 to 503; f) 548 to 571; g) 673 to 699; h) 717 to 737; i) 836 to 905; j) 944 to 964; k) 1013 to 1093; and l) 1353 to 1427, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1, the double stranded region comprises: i) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 2 (5′ UCAAUAAAAAGAAGGAGCUUAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 63 (5′ AAGCUCCUUCUUUUUAUUGA 3′); ii) an anti-sense of nucleotide sequence according to SEQ ID NO: 3 (5′ UAAAUUUUUACAUCGUCUAACA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 64 (5′ UUAGACGAUGUAAAAAUUUA 3′); iii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 4 (5′ UAUAAAAAGACUGAUCAAAUAU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 65 (5′ AUUUGAUCAGUCUUUUUAUA 3′); iv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 11 (5′ UGUAUAACCUUCCAUUUUGAGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 72 (5′ UCAAAAUGGAAGGUUAUACA 3′); v) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 13 (5′ UUUGAUUUUAUAGAGUAUAACC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 74 (5′ UUAUACUCUAUAAAAUCAAA 3′); vi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 14 (5′ UAAAGAAGGAGCUUAAUUGUGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 75 (5′ ACAAUUAAGCUCCUUCUUUA 3′); vii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 15 (5′ UAUAAAAAGAAGGAGCUUAAUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 76 (5′ UUAAGCUCCUUCUUUUUAUA 3′); viii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 16 (5′ UAAUAAAAAGAAGGAGCUUAAU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 77 (5′ UAAGCUCCUUCUUUUUAUUA 3′); ix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 17 (5′ UAAAUAACUAGAGGAACAAUAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 78 (5′ AUUGUUCCUCUAGUUAUUUA 3′); x) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 18 (5′ UAAAUCUUGAUUUUGGCUCUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 79 (5′ AGAGCCAAAAUCAAGAUUUA 3′); xi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 19 (5′ UCAUAGCAAAUCUUGAUUUUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 80 (5′ AAAAUCAAGAUUUGCUAUGA 3′); xii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 20 (5′ UUUGAUUUUGGCUCUGGAGAUA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 81 (5′ UCUCCAGAGCCAAAAUCAAA 3′); xiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 21 (5′ UAUCGUCUAACAUAGCAAAUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 82 (5′ AUUUGCUAUGUUAGACGAUA 3′); xiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 22 (5′ UAUUUUUACAUCGUCUAACAUA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 83 (5′ UGUUAGACGAUGUAAAAAUA 3′); xv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 23 (5′ UAAAAUUUUUACAUCGUCUAAC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 84 (5′ UAGACGAUGUAAAAAUUUUA 3′); xvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 24 (5′ UGAUAGAUCAUAAAAAGACUGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 85 (5′ AGUCUUUUUAUGAUCUAUCA 3′); xvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 25 (5′ UUAAAAAGACUGAUCAAAUAUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 86 (5′ UAUUUGAUCAGUCUUUUUAA 3′); xviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 26 (5′ UAUAGAUCAUAAAAAGACUGAU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 87 (5′ CAGUCUUUUUAUGAUCUAUA 3′); xix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 27 (5′ UUAGUUUAUAUGUAGUUCUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 88 (5′ AAGAACUACAUAUAAACUAA 3′); xx) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 28 (5′ UUUUAUAUGUAGUUCUUCUCAG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 89 (5′ GAGAAGAACUACAUAUAAAA 3′); xxi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 29 (5′ UAUUUUUGACUUGUAGUUUAUA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 90 (5′ UAAACUACAAGUCAAAAAUA 3′); xxii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 30 (5′ UUUAAGUUAGUUAGUUGCUCUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 91 (5′ GAGCAACUAACUAACUUAAA 3′); xxiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 31 (5′ UAUUAAGUUAGUUAGUUGCUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 92 (5′ AGCAACUAACUAACUUAAUA 3′); xxiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 32 (5′ UUUGAUUUUGAAUUAAGUUAGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 93 (5′ UAACUUAAUUCAAAAUCAAA 3′); xxv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 33 (5′ UUUCUAAAUAUUUCACUUUUUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 94 (5′ AAAAGUGAAAUAUUUAGAAA 3′); xxvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 34 (5′ UUUAGUUAGUUGCUCUUCUAAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 95 (5′ UAGAAGAGCAACUAACUAAA 3′); xxvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 35 (5′ UCUAUUAUCUUGUUUUUCUACA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 96 (5′ UAGAAAAACAAGAUAAUAGA 3′); xxviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 36 (5′ UAUGCUAUUAUCUUGUUUUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 97 (5′ AAAAACAAGAUAAUAGCAUA 3′); xxix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 37 (5′ UAAGAUAGAGAAAUUUCUGUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 98 (5′ ACAGAAAUUUCUCUAUCUUA 3′); xxx) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 38 (5′ UGAGAAAUUUCUGUGGGUUCUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 99 (5′ GAACCCACAGAAAUUUCUCA 3′); xxxi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 39 (5′ UCUGAAGAAAGGGAGUAGUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 100 (5′ AACUACUCCCUUUCUUCAGA 3′); xxxii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 40 (5′ UAAAACUUGAGAGUUGCUGGGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 101 (5′ CCAGCAACUCUCAAGUUUUA 3′); xxxiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 41 (5′ UUUGAAUUAAUGUCCAUGGACU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 102 (5′ UCCAUGGACAUUAAUUCAAA 3′); xxxiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 42 (5′ UAAACCAUAUUUGUAGUUCUCC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 103 (5′ AGAACUACAAAUAUGGUUUA 3′); xxxv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 43 (5′ UUAAUUAGAUUGCUUCACUAUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 104 (5′ UAGUGAAGCAAUCUAAUUAA 3′); xxxvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 44 (5′ UUAUAAUGUUUGUUGUCUUUCC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 105 (5′ AAAGACAACAAACAUUAUAA 3′); xxxvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 45 (5′ UAUAUAAUGUUUGUUGUCUUUC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 106 (5′ AAGACAACAAACAUUAUAUA 3′); xxxviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 46 (5′ UAAAGAAUAUUCAAUAUAAUGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 107 (5′ AUUAUAUUGAAUAUUCUUUA 3′); or xxxix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 200 (5′ UUUCAAAGCUUUCUGAAUCUGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 235 (5′ AGAUUCAGAAAGCUUUGAAA 3′). 
     In some embodiments of the isolated oligonucleotide of the present disclosure, wherein the sense strand comprises a sequence that is identical to a region between any one of the nucleotide positions selected from: a) 54 to 74; b) 148 to 179; c) 246 to 282; d) 337 to 414; e) 433 to 495; and f) 522 to 542; g) 617 to 637; h) 838 to 858; and i) 1361 to 1381, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1, the double stranded region comprises: i) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 5 (5′ UGACAUAUUCUUUACCUCUUCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 66 (5′ AAGAGGUAAAGAAUAUGUCA 3′); ii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 6 (5′ UUUUAAGUGAAGUUACUUCUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 67 (5′ AGAAGUAACUUCACUUAAAA 3′); iii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 9 (5′ UGAAAAACUUGAGAGUUGCUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 70 (5′ AGCAACUCUCAAGUUUUUCA 3′); iv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 12 (5′ UUUUAUAGAGUAUAACCUUCCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 73 (5′ GAAGGUUAUACUCUAUAAAA 3′); v) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 47 (5′ UAAAAAGAAGGAGCUUAAUUGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 108 (5′ AAUUAAGCUCCUUCUUUUUA 3′); vi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 48 (5′ UUUUACAUCGUCUAACAUAGCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 109 (5′ CUAUGUUAGACGAUGUAAAA 3′); vii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 49 (5′ UUUUUACAUCGUCUAACAUAGC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 110 (5′ UAUGUUAGACGAUGUAAAAA 3′); viii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 50 (5′ UCUAACAUAGCAAAUCUUGAUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 111 (5′ UCAAGAUUUGCUAUGUUAGA 3′); ix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 51 (5′ UUUGAAAUAUGUCAUUAAUUUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 112 (5′ AAUUAAUGACAUAUUUCAAA 3′); x) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 52 (5′ UCAAAUAUGUUGAGUUUUUGAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 113 (5′ CAAAAACUCAACAUAUUUGA 3′); xi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 53 (5′ UAUGUAGUUCUUCUCAGUUCCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 114 (5′ GAACUGAGAAGAACUACAUA 3′); xii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 54 (5′ UUUAUAUGUAGUUCUUCUCAGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 115 (5′ UGAGAAGAACUACAUAUAAA 3′); xiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 55 (5′ UCAAGUGACAUAUUCUUUACCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 116 (5′ GUAAAGAAUAUGUCACUUGA 3′); xiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 56 (5′ UUUGAGUUGAGUUCAAGUGACA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 117 (5′ UCACUUGAACUCAACUCAAA 3′); xv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 57 (5′ UAAGUUAGUUAGUUGCUCUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 118 (5′ AAGAGCAACUAACUAACUUA 3′); xvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 58 (5′ UGAAUUAAGUUAGUUAGUUGCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 119 (5′ CAACUAACUAACUUAAUUCA 3′); xvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 59 (5′ UGUUGAAGUAGAAUUUUUUCUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 120 (5′ GAAAAAAUUCUACUUCAACA 3′); xviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 60 (5′ UUUGUUGAAGUAGAAUUUUUUC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 121 (5′ AAAAAUUCUACUUCAACAAA 3′); xix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 61 (5′ UUUCACUUUUUGUUGAAGUAGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 122 (5′ UACUUCAACAAAAAGUGAAA 3′); or xx) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 62 (5′ UUUUAUUUGACUAUGCUGUUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 123 (5′ AACAGCAUAGUCAAAUAAAA 3′). 
     In some embodiments, the isolated oligonucleotide of the present disclosure attenuates expression of the ANGPTL-3 mRNA by 20% to 50% (e.g., between 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 40% to 45% or 45% to 50%), at a dose of 0.02 nM. 
     In some embodiments of the isolated oligonucleotide of the present disclosure that attenuate expression of the ANGPTL-3 mRNA by 20% to 50%, at a dose of 0.02 nM, the double stranded region comprises: i) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 3 (5′ UAAAUUUUUACAUCGUCUAACA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 64 (5′ UUAGACGAUGUAAAAAUUUA 3′); ii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 4 (5′ UAUAAAAAGACUGAUCAAAUAU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 65 (5′ AUUUGAUCAGUCUUUUUAUA 3′); iii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 7 (5′ UUUUUAAGUGAAGUUACUUCUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 68 (5′ GAAGUAACUUCACUUAAAAA 3′); iv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 8 (5′ UGAAGAUAGAGAAAUUUCUGUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 69 (5′ CAGAAAUUUCUCUAUCUUCA 3′); v) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 9 (5′ UGAAAAACUUGAGAGUUGCUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 70 (5′ AGCAACUCUCAAGUUUUUCA 3′); vi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 10 (5′ UUAAUGUUUGUUGUCUUUCCAG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 71 (5′ GGAAAGACAACAAACAUUAA 3′); vii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 12 (5′ UUUUAUAGAGUAUAACCUUCCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 73 (5′ GAAGGUUAUACUCUAUAAAA 3′); viii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 14 (5′ UAAAGAAGGAGCUUAAUUGUGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 75 (5′ ACAAUUAAGCUCCUUCUUUA 3′); ix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 16 (5′ UAAUAAAAAGAAGGAGCUUAAU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 77 (5′ UAAGCUCCUUCUUUUUAUUA 3′); x) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 17 (5′ UAAAUAACUAGAGGAACAAUAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 78 (5′ AUUGUUCCUCUAGUUAUUUA 3′); xi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 20 (5′ UUUGAUUUUGGCUCUGGAGAUA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 81 (5′ UCUCCAGAGCCAAAAUCAAA 3′); xii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 21 (5′ UAUCGUCUAACAUAGCAAAUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 82 (5′ AUUUGCUAUGUUAGACGAUA 3′); xiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 24 (5′ UGAUAGAUCAUAAAAAGACUGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 85 (5′ AGUCUUUUUAUGAUCUAUCA 3′); xiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 25 (5′ UUAAAAAGACUGAUCAAAUAUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 86 (5′ UAUUUGAUCAGUCUUUUUAA 3′); xv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 26 (5′ UAUAGAUCAUAAAAAGACUGAU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 87 (5′ CAGUCUUUUUAUGAUCUAUA 3′); xvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 27 (5′ UUAGUUUAUAUGUAGUUCUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 88 (5′ AAGAACUACAUAUAAACUAA 3′); xvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 30 (5′ UUUAAGUUAGUUAGUUGCUCUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 91 (5′ GAGCAACUAACUAACUUAAA 3′); xiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 32 (5′ UUUGAUUUUGAAUUAAGUUAGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 93 (5′ UAACUUAAUUCAAAAUCAAA 3′); xix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 33 (5′ UUUCUAAAUAUUUCACUUUUUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 94 (5′ AAAAGUGAAAUAUUUAGAAA 3′); xx) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 35 (5′ UCUAUUAUCUUGUUUUUCUACA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 96 (5′ UAGAAAAACAAGAUAAUAGA 3′); xxi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 37 (5′ UAAGAUAGAGAAAUUUCUGUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 98 (5′ ACAGAAAUUUCUCUAUCUUA 3′); xxii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 38 (5′ UGAGAAAUUUCUGUGGGUUCUU 3′), and an sense strand of nucleotide sequence according to SEQ ID NO: 99 (5′ GAACCCACAGAAAUUUCUCA 3′); xxiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 39 (5′ UCUGAAGAAAGGGAGUAGUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 100 (5′ AACUACUCCCUUUCUUCAGA 3′); xxiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 40 (5′ UAAAACUUGAGAGUUGCUGGGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 101 (5′ CCAGCAACUCUCAAGUUUUA 3′); xxv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 41 (5′ UUUGAAUUAAUGUCCAUGGACU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 102 (5′ UCCAUGGACAUUAAUUCAAA 3′); xxvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 42 (5′ UAAACCAUAUUUGUAGUUCUCC 3′), and an anti-sense strand of nucleotide sequence according to SEQ ID NO: 103 (5′ AGAACUACAAAUAUGGUUUA 3′); xxvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 5 (5′ UGACAUAUUCUUUACCUCUUCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 66 (5′ AAGAGGUAAAGAAUAUGUCA 3′); xxviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 44 (5′ UUAUAAUGUUUGUUGUCUUUCC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 105 (5′ AAAGACAACAAACAUUAUAA 3′); xxix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 47 (5′ UAAAAAGAAGGAGCUUAAUUGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 108 (5′ AAUUAAGCUCCUUCUUUUUA 3′); xxx) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 48 (5′ UUUUACAUCGUCUAACAUAGCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 109 (5′ CUAUGUUAGACGAUGUAAAA 3′); xxxi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 49 (5′ UUUUUACAUCGUCUAACAUAGC 3′), and an anti-sense strand of nucleotide sequence according to SEQ ID NO: 110 (5′ UAUGUUAGACGAUGUAAAAA 3′); xxxii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 50 (5′ UCUAACAUAGCAAAUCUUGAUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 111 (5′ UCAAGAUUUGCUAUGUUAGA 3′); xxxiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 51 (5′ UUUGAAAUAUGUCAUUAAUUUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 112 (5′ AAUUAAUGACAUAUUUCAAA 3′); xxxiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 52 (5′ UCAAAUAUGUUGAGUUUUUGAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 113 (5′ CAAAAACUCAACAUAUUUGA 3′); xxxv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 53 (5′ UAUGUAGUUCUUCUCAGUUCCU 3′), and an anti-sense strand of nucleotide sequence according to SEQ ID NO: 114 (5′ GAACUGAGAAGAACUACAUA 3′); xxxvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 54 (5′ UUUAUAUGUAGUUCUUCUCAGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 115 (5′ UGAGAAGAACUACAUAUAAA 3′); xxxvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 55 (5′ UCAAGUGACAUAUUCUUUACCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 116 (5′ GUAAAGAAUAUGUCACUUGA 3′); xxxviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 56 (5′ UUUGAGUUGAGUUCAAGUGACA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 117 (5′ UCACUUGAACUCAACUCAAA 3′); xxxix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 58 (5′ UGAAUUAAGUUAGUUAGUUGCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 119 (5′ CAACUAACUAACUUAAUUCA 3′); 
     xL) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 59 (5′ UGUUGAAGUAGAAUUUUUUCUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 120 (5′ GAAAAAAUUCUACUUCAACA 3′); xLi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 60 (5′ UUUGUUGAAGUAGAAUUUUUUC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 121 (5′ AAAAAUUCUACUUCAACAAA 3′); xLii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 61 (5′ UUUCACUUUUUGUUGAAGUAGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 122 (5′ UACUUCAACAAAAAGUGAAA 3′); xLiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 62 (5′ UUUUAUUUGACUAUGCUGUUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 123 (5′ AACAGCAUAGUCAAAUAAAA 3′); xLiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 28 (5′ UUUUAUAUGUAGUUCUUCUCAG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 89 (5′ GAGAAGAACUACAUAUAAAA 3′); or xLv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 200 (5′ UUUCAAAGCUUUCUGAAUCUGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 235 (5′ AGAUUCAGAAAGCUUUGAAA 3′). 
     In some embodiments, the isolated oligonucleotide of the present disclosure attenuates expression of the ANGPTL-3 mRNA by at least 50% (e.g., 50% to 55%, 55% to 60%, 60% to 65%, 65% to 70%, 70% to 75%, 75% to 80%, 80% to 85%, 85% to 90%, 90% to 95% or 95% to 99%, 99% to 100%), at a dose of 0.02 nM. 
     In some embodiments of the isolated oligonucleotide of the present disclosure that attenuate expression of the ANGPTL-3 mRNA by at least 50%, at a dose of 0.02 nM, the double stranded region comprises: i) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 2 (5′ UCAAUAAAAAGAAGGAGCUUAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 63 (5′ AAGCUCCUUCUUUUUAUUGA 3′); ii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 6 (5′ UUUUAAGUGAAGUUACUUCUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 67 (5′ AGAAGUAACUUCACUUAAAA 3′); iii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 11 (5′ UGUAUAACCUUCCAUUUUGAGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 72 (5′ UCAAAAUGGAAGGUUAUACA 3′); iv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 13 (5′ UUUGAUUUUAUAGAGUAUAACC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 74 (5′ UUAUACUCUAUAAAAUCAAA 3′); v) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 15 (5′ UAUAAAAAGAAGGAGCUUAAUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 76 (5′ UUAAGCUCCUUCUUUUUAUA 3′); vi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 18 (5′ UAAAUCUUGAUUUUGGCUCUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 79 (5′ AGAGCCAAAAUCAAGAUUUA 3′); vii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 19 (5′ UCAUAGCAAAUCUUGAUUUUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 80 (5′ AAAAUCAAGAUUUGCUAUGA 3′); viii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 22 (5′ UAUUUUUACAUCGUCUAACAUA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 83 (5′ UGUUAGACGAUGUAAAAAUA 3′); ix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 23 (5′ UAAAAUUUUUACAUCGUCUAAC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 84 (5′ UAGACGAUGUAAAAAUUUUA 3′); x) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 29 (5′ UAUUUUUGACUUGUAGUUUAUA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 90 (5′ UAAACUACAAGUCAAAAAUA 3′); xi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 31 (5′ UAUUAAGUUAGUUAGUUGCUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 92 (5′ AGCAACUAACUAACUUAAUA 3′); xii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 34 (5′ UUUAGUUAGUUGCUCUUCUAAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 95 (5′ UAGAAGAGCAACUAACUAAA 3′); xiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 36 (5′ UAUGCUAUUAUCUUGUUUUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 97 (5′ AAAAACAAGAUAAUAGCAUA 3′); xiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 45 (5′ UAUAUAAUGUUUGUUGUCUUUC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 106 (5′ AAGACAACAAACAUUAUAUA 3′); xv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 57 (5′ UAAGUUAGUUAGUUGCUCUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 118 (5′ AAGAGCAACUAACUAACUUA 3′); or xvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 46 (5′ UAAAGAAUAUUCAAUAUAAUGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 107 (5′ AUUAUAUUGAAUAUUCUUUA 3′). 
     In some embodiments, the isolated oligonucleotide of the present disclosure attenuates expression of the ANGPTL-3 mRNA by 50% to 75% (e.g., between 50% to 55%, 55% to 60%, 60% to 65%, 65% to 70% or 70% to 75%), at a dose of 0.1 nM. 
     In some embodiments of the isolated oligonucleotide of the present disclosure that attenuate expression of the ANGPTL-3 mRNA by 50% to 75%, at a dose of 0.1 nM, the double stranded region comprises: i) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 4 (5′ UAUAAAAAGACUGAUCAAAUAU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 65 (5′ AUUUGAUCAGUCUUUUUAUA 3′); ii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 10 (5′ UUAAUGUUUGUUGUCUUUCCAG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 71 (5′ GGAAAGACAACAAACAUUAA 3′); iii) anti-sense strand of nucleotide sequence according to SEQ ID NO: 12 (5′ UUUUAUAGAGUAUAACCUUCCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 73 (5′ GAAGGUUAUACUCUAUAAAA 3′); iv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 16 (5′ UAAUAAAAAGAAGGAGCUUAAU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 77 (5′ UAAGCUCCUUCUUUUUAUUA 3′); v) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 24 (5′ UGAUAGAUCAUAAAAAGACUGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 85 (5′ AGUCUUUUUAUGAUCUAUCA 3′); vi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 27 (5′ UUAGUUUAUAUGUAGUUCUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 88 (5′ AAGAACUACAUAUAAACUAA 3′); vii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 30 (5′ UUUAAGUUAGUUAGUUGCUCUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 91 (5′ GAGCAACUAACUAACUUAAA 3′); viii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 32 (5′ UUUGAUUUUGAAUUAAGUUAGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 93 (5′ UAACUUAAUUCAAAAUCAAA 3′); ix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 35 (5′ UCUAUUAUCUUGUUUUUCUACA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 96 (5′ UAGAAAAACAAGAUAAUAGA 3′); x) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 37 (5′ UAAGAUAGAGAAAUUUCUGUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 98 (5′ ACAGAAAUUUCUCUAUCUUA 3′); xi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 38 (5′ UGAGAAAUUUCUGUGGGUUCUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 99 (5′ GAACCCACAGAAAUUUCUCA 3′); xii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 39 (5′ UCUGAAGAAAGGGAGUAGUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 100 (5′ AACUACUCCCUUUCUUCAGA 3′); xiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 41 (5′ UUUGAAUUAAUGUCCAUGGACU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 102 (5′ UCCAUGGACAUUAAUUCAAA 3′); xiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 42 (5′ UAAACCAUAUUUGUAGUUCUCC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 103 (5′ AGAACUACAAAUAUGGUUUA 3′); xv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 44 (5′ UUAUAAUGUUUGUUGUCUUUCC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 105 (5′ AAAGACAACAAACAUUAUAA 3′); xvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 46 (5′ UAAAGAAUAUUCAAUAUAAUGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 107 (5′ AUUAUAUUGAAUAUUCUUUA 3′); xvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 48 (5′ UUUUACAUCGUCUAACAUAGCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 109 (5′ CUAUGUUAGACGAUGUAAAA 3′); xviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 49 (5′ UUUUUACAUCGUCUAACAUAGC 3′), and an anti-sense strand of nucleotide sequence according to SEQ ID NO: 110 (5′ UAUGUUAGACGAUGUAAAAA 3′); xix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 52 (5′ UCAAAUAUGUUGAGUUUUUGAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 113 (5′ CAAAAACUCAACAUAUUUGA 3′); xx) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 53 (5′ UAUGUAGUUCUUCUCAGUUCCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 114 (5′ GAACUGAGAAGAACUACAUA 3′); xxi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 56 (5′ UUUGAGUUGAGUUCAAGUGACA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 117 (5′ UCACUUGAACUCAACUCAAA 3′); xxii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 60 (5′ UUUGUUGAAGUAGAAUUUUUUC 3′), and an anti-sense strand of nucleotide sequence according to SEQ ID NO: 121 (5′ AAAAAUUCUACUUCAACAAA 3′); xxiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 61 (5′ UUUCACUUUUUGUUGAAGUAGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 122 (5′ UACUUCAACAAAAAGUGAAA 3′); xxiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 19 (5′ UCAUAGCAAAUCUUGAUUUUGG 3′), and an anti-sense strand of nucleotide sequence according to SEQ ID NO: 80 (5′ AAAAUCAAGAUUUGCUAUGA 3′); or xxv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 58 (5′ UGAAUUAAGUUAGUUAGUUGCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 119 (5′ CAACUAACUAACUUAAUUCA 3′). 
     In some embodiments, the isolated oligonucleotide of the present disclosure attenuates expression of the ANGPTL-3 mRNA by at least 75% (e.g., 75% to 80%, 805 to 85%, 85% to 90%, 90% to 95%, 95% to 99% or 99% to 100%), at a dose of 0.1 nM. 
     In some embodiments of the isolated oligonucleotide of the present disclosure that attenuates expression of the ANGPTL-3 mRNA by at least 75%, at a dose of 0.1 nM, the double stranded region comprises: i) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 2 (5′ UCAAUAAAAAGAAGGAGCUUAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 63 (5′ AAGCUCCUUCUUUUUAUUGA 3′); ii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 3 (5′ UAAAUUUUUACAUCGUCUAACA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 64 (5′ UUAGACGAUGUAAAAAUUUA 3′); iii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 6 (5′ UUUUAAGUGAAGUUACUUCUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 67 (5′ AGAAGUAACUUCACUUAAAA 3′); iv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 8 (5′ UGAAGAUAGAGAAAUUUCUGUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 69 (5′ CAGAAAUUUCUCUAUCUUCA 3′); v) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 9 (5′ UGAAAAACUUGAGAGUUGCUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 70 (5′ AGCAACUCUCAAGUUUUUCA 3′); vi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 11 (5′ UGUAUAACCUUCCAUUUUGAGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 72 (5′ UCAAAAUGGAAGGUUAUACA 3′); vii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 13 (5′ UUUGAUUUUAUAGAGUAUAACC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 74 (5′ UUAUACUCUAUAAAAUCAAA 3′); viii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 14 (5′ UAAAGAAGGAGCUUAAUUGUGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 75 (5′ ACAAUUAAGCUCCUUCUUUA 3′); 
     ix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 15 (5′ UAUAAAAAGAAGGAGCUUAAUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 76 (5′ UUAAGCUCCUUCUUUUUAUA 3′); x) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 17 (5′ UAAAUAACUAGAGGAACAAUAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 78 (5′ AUUGUUCCUCUAGUUAUUUA 3′); xi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 18 (5′ UAAAUCUUGAUUUUGGCUCUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 79 (5′ AGAGCCAAAAUCAAGAUUUA 3′); xii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 20 (5′ UUUGAUUUUGGCUCUGGAGAUA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 81 (5′ UCUCCAGAGCCAAAAUCAAA 3′); xiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 21 (5′ UAUCGUCUAACAUAGCAAAUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 82 (5′ AUUUGCUAUGUUAGACGAUA 3′); xiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 22 (5′ UAUUUUUACAUCGUCUAACAUA 3′), and an anti-sense strand of nucleotide sequence according to SEQ ID NO: 83 (5′ UGUUAGACGAUGUAAAAAUA 3′); xv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 23 (5′ UAAAAUUUUUACAUCGUCUAAC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 84 (5′ UAGACGAUGUAAAAAUUUUA 3′); xvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 25 (5′ UUAAAAAGACUGAUCAAAUAUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 86 (5′ UAUUUGAUCAGUCUUUUUAA 3′); xvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 26 (5′ UAUAGAUCAUAAAAAGACUGAU 3′), and an anti-sense strand of nucleotide sequence according to SEQ ID NO: 87 (5′ CAGUCUUUUUAUGAUCUAUA 3′); xviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 29 (5′ UAUUUUUGACUUGUAGUUUAUA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 90 (5′ UAAACUACAAGUCAAAAAUA 3′); xix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 31 (5′ UAUUAAGUUAGUUAGUUGCUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 92 (5′ AGCAACUAACUAACUUAAUA 3′); xx) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 33 (5′ UUUCUAAAUAUUUCACUUUUUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 94 (5′ AAAAGUGAAAUAUUUAGAAA 3′); xxi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 34 (5′ UUUAGUUAGUUGCUCUUCUAAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 95 (5′ UAGAAGAGCAACUAACUAAA 3′); xxii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 36 (5′ UAUGCUAUUAUCUUGUUUUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 97 (5′ AAAAACAAGAUAAUAGCAUA 3′); xxiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 40 (5′ UAAAACUUGAGAGUUGCUGGGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 101 (5′ CCAGCAACUCUCAAGUUUUA 3′); xxiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 43 (5′ UUAAUUAGAUUGCUUCACUAUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 104 (5′ UAGUGAAGCAAUCUAAUUAA 3′); xxv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 45 (5′ UAUAUAAUGUUUGUUGUCUUUC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 106 (5′ AAGACAACAAACAUUAUAUA 3′); xxvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 47 (5′ UAAAAAGAAGGAGCUUAAUUGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 108 (5′ AAUUAAGCUCCUUCUUUUUA 3′); xxvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 50 (5′ UCUAACAUAGCAAAUCUUGAUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 111 (5′ UCAAGAUUUGCUAUGUUAGA 3′); xxviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 51 (5′ UUUGAAAUAUGUCAUUAAUUUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 112 (5′ AAUUAAUGACAUAUUUCAAA 3′); xxix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 54 (5′ UUUAUAUGUAGUUCUUCUCAGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 115 (5′ UGAGAAGAACUACAUAUAAA 3′); xxx) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 55 (5′ UCAAGUGACAUAUUCUUUACCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 116 (5′ GUAAAGAAUAUGUCACUUGA 3′); xxxi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 57 (5′ UAAGUUAGUUAGUUGCUCUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 118 (5′ AAGAGCAACUAACUAACUUA 3′); xxxii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 5 (5′ UGACAUAUUCUUUACCUCUUCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 66 (5′ AAGAGGUAAAGAAUAUGUCA 3′); xxxiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 59 (5′ UGUUGAAGUAGAAUUUUUUCUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 120 (5′ GAAAAAAUUCUACUUCAACA 3′); xxxiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 62 (5′ UUUUAUUUGACUAUGCUGUUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 123 (5′ AACAGCAUAGUCAAAUAAAA 3′); xxxv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 7 (5′ UUUUUAAGUGAAGUUACUUCUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 68 (5′ GAAGUAACUUCACUUAAAAA 3′); xxxvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 28 (5′ UUUUAUAUGUAGUUCUUCUCAG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 89 (5′ GAGAAGAACUACAUAUAAAA 3′); or xxxvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 200 (5′ UUUCAAAGCUUUCUGAAUCUGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 235 (5′ AGAUUCAGAAAGCUUUGAAA 3′). 
     The present disclosure also provides a vector encoding an isolated oligonucleotide disclosed herein. 
     The present disclosure also provides a delivery system comprising an isolated oligonucleotide or vector disclosed herein. 
     The present disclosure also provides a pharmaceutical composition comprising an isolated oligonucleotide, vector or delivery system disclosed herein, and a pharmaceutically acceptable carrier, diluent or excipient. 
     The present disclosure also provides a kit comprising an isolated oligonucleotide, vector, delivery system or a pharmaceutical composition disclosed herein. 
     The present disclosure also provides a method of inhibiting or downregulating the expression or level of ANGPTL-3 in a subject in need thereof, wherein the method comprises administering to the subject an effective amount an isolated oligonucleotide, vector, delivery system or a pharmaceutical composition disclosed herein. 
     The present disclosure also provides a method of inhibiting or downregulating the expression or level of ANGPTL-3 in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a first and at least a second oligonucleotides disclosed herein, wherein the first and at least second oligonucleotides comprise different sequences. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG.  1    is a graph showing the efficacy of siRNA compounds listed in Table 2, Set 1 and Set 2, in silencing human Angptl3 in cultured Huh-7 cells at 0.02 nM. The compounds were transfected into cells at 0.02 nM concentration. Data is presented as % of human Angptl3 mRNA remaining relative to mock transfection when normalized to Gapdh mRNA levels (Mean, +/−SEM). Each bar represents a single compound tested, and the grid line on X-axis separates the two sets of compounds in Table 2, Set 1 and Set 2, respectively. 
         FIG.  2    is a graph showing the efficacy of siRNA compounds listed in Table 2, Set 1 and Set 2, in silencing human Angptl3 in cultured Huh-7 cells at 0.1 nM. The compounds were transfected into cells at 0.1 nM concentration. Data is presented as % of human Angptl3 mRNA remaining relative to mock transfection when normalized to Gapdh mRNA levels (Mean, +/−SEM). Each bar represents a single compound tested, and the grid line on X-axis separates the two sets of compounds in Table 2, Set 1 and Set 2, respectively. 
         FIGS.  3 A- 3 R  are graphs showing dose-response curves for indicated human Angptl3 siRNA compounds. The X-axis indicates the concentration (picomolar) of the indicated compounds that were transfected into Huh-7 cells. The IC 50  was calculated using the three parameter Log (inhibitor) vs. response formula and is indicated above each graph. The Y-axis indicates the % of human Angptl3 mRNA remaining relative to mock transfection when normalized to Gapdh mRNA levels (Mean, +/−SEM). 
         FIG.  4    is a graph showing in vivo potency of the indicated siRNA compounds, containing GalNAc conjugations, in silencing human Angptl3 in a BALB/c mouse model after administration of 0.5 mg/kg dosage of the indicated compound. Liver biopsies were taken on day 5 for mRNA expression analysis via RT-qPCR. Data is represented as % of human Angptl3 mRNA remaining relative to PBS groups when normalized to Neomycin-resistant (NeoR) gene mRNA levels (Mean, +/−SD). 
         FIG.  5    is a graph depicting in vivo dose response of the indicated siRNA compounds, containing GalNAc conjugations, in silencing human Angptl3 in a BALB/c mouse model after administration of 0.25 mg/kg (squares), 0.5 mg/kg (circles), and 1 mg/kg (triangles) of the indicated compound. Data is represented as % of human Angptl3 mRNA remaining relative to PBS groups when normalized to NeoR mRNA levels (Mean, +/−SD). 
         FIGS.  6 A- 6 B  are two graphs depicting in vivo compound potency and duration evaluations of the indicated siRNA compounds, containing chemical modifications and GalNAc conjugations, in a humanized transgenic mice model that expresses human Angplt3. Liver biopsies were taken on day 14 after compound administration for mRNA expression analysis via RT-qPCR. Serum hsANGPTL3 protein levels were analyzed on day −1, 4, 7, and 14 via ELISA.  FIG.  6 A  shows percentage human Angptl3 mRNA remaining in the liver compared to PBS control.  FIG.  6 B  shows absolute values of serum ANGPLT3 protein concentration compared to PBS control. 
     
    
    
     DETAILED DESCRIPTION 
     The present disclosure provides isolated oligonucleotides (oligonucleotide(s)) that form a double stranded region, preferably small interfering RNAs (siRNAs), that can decrease ANGPTL-3 mRNA expression, in turn leading to a decrease in the degree of ANGPTL-3 protein expression in target cells. The oligonucleotides disclosed herein can have therapeutic application in regulating the expression of ANGPTL-3, for treatment of diseases, including but not limited to cardiovascular disease (CVD), atherosclerosis, hypercholesterolemia, hyperlipidemia or hypertriglyceridemia. 
     The present disclosure has identified specific regions within the ANGPTL-3 mRNA, that provide targets for binding double stranded oligonucleotides, e.g., siRNA, leading to reduction in level of expression of the ANGPTL-3 mRNA. 
     The ANGPTL-3 mRNA sequence described herein, is an mRNA sequence of ANGPTL-3 according to accession no. NM_014495.4: 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 1) 
                   
               
               
                    1 agaagaaaac agttccacgt tgcttgaaat tgaaaatcaa gataaaaatg ttcacaatta 
                   
               
               
                   
               
               
                   61 agctccttct ttttattgtt cctctagtta tttcctccag aattgatcaa gacaattcat 
               
               
                   
               
               
                  121 catttgattc tctatctcca gagccaaaat caagatttgc tatgttagac gatgtaaaaa 
               
               
                   
               
               
                  181 ttttagccaa tggcctcctt cagttgggac atggtcttaa agactttgte cataagacga 
               
               
                   
               
               
                  241 agggccaaat taatgacata tttcaaaaac tcaacatatt tgatcagtct ttttatgatc 
               
               
                   
               
               
                  301 tatcgctgca aaccagtgaa atcaaagaag aagaaaagga actgagaaga actacatata 
               
               
                   
               
               
                  361 aactacaagt caaaaatgaa gaggtaaaga atatgtcact tgaactcaac tcaaaacttg 
               
               
                   
               
               
                  421 aaagcctcct agaagaaaaa attctacttc aacaaaaagt gaaatattta gaagagcaac 
               
               
                   
               
               
                  481 taactaactt aattcaaaat caacctgaaa ctccagaaca cccagaagta acttcactta 
               
               
                   
               
               
                  541 aaacttttgt agaaaaacaa gataatagca tcaaagacct tctccagacc gtggaagacc 
               
               
                   
               
               
                  601 aatataaaca attaaaccaa cagcatagtc aaataaaaga aatagaaaat cagetcagaa 
               
               
                   
               
               
                  661 ggactagtat tcaagaaccc acagaaattt ctctatcttc caagccaaga gcaccaagaa 
               
               
                   
               
               
                  721 ctactccctt tettcagttg aatgaaataa gaaatgtaaa acatgatggc attcctgctg 
               
               
                   
               
               
                  781 aatgtaccac catttataac agaggtgaac atacaagtgg catgtatgcc atcagaccca 
               
               
                   
               
               
                  841 gcaactctca agtttttcat gtctactgtg atgttatatc aggtagtcca tggacattaa 
               
               
                   
               
               
                  901 ttcaacatcg aatagatgga tcacaaaact tcaatgaaac gtgggagaac tacaaatatg 
               
               
                   
               
               
                  961 gttttgggag gcttgatgga gaattttggt tgggcctaga gaagatatac tccatagtga 
               
               
                   
               
               
                 1021 agcaatctaa ttatgtttta cgaattgagt tggaagactg gaaagacaac aaacattata 
               
               
                   
               
               
                 1081 ttgaatattc tttttacttg ggaaatcacg aaaccaacta tacgctacat ctagttgcga 
               
               
                   
               
               
                 1141 ttactggcaa tgtccccaat gcaatcccgg aaaacaaaga tttggtgttt tctacttggg 
               
               
                   
               
               
                 1201 atcacaaagc aaaaggacac ttcaactgte cagagggtta ttcaggaggc tggtggtggc 
               
               
                   
               
               
                 1261 atgatgagtg tggagaaaac aacctaaatg gtaaatataa caaaccaaga gcaaaatcta 
               
               
                   
               
               
                 1321 agccagagag gagaagagga ttatcttgga agtctcaaaa tggaaggtta tactctataa 
               
               
                   
               
               
                 1381 aatcaaccaa aatgttgatc catccaacag attcagaaag ctttgaatga actgaggcaa 
               
               
                   
               
               
                 1441 atttaaaagg caataattta aacattaacc tcattccaag ttaatgtggt ctaataatct 
               
               
                   
               
               
                 1501 ggtattaaat ccttaagaga aagcttgaga aatagatttt ttttatctta aagtcactgt 
               
               
                   
               
               
                 1561 ctatttaaga ttaaacatac aatcacataa ccttaaagaa taccgtttac atttctcaat 
               
               
                   
               
               
                 1621 caaaattctt ataatactat ttgttttaaa ttttgtgatg tgggaatcaa ttttagatgg 
               
               
                   
               
               
                 1681 tcacaatcta gattataatc aataggtgaa cttattaaat aacttttcta aataaaaaat 
               
               
                   
               
               
                 1741 ttagagactt ttattttaaa aggcatcata tgagctaata tcacaacttt cccagtttaa 
               
               
                   
               
               
                 1801 aaaactagta ctcttgttaa aactctaaac ttgactaaat acagaggact ggtaattgta 
               
               
                   
               
               
                 1861 cagttcttaa atgttgtagt attaatttca aaactaaaaa tcgtcagcac agagtatgtg 
               
               
                   
               
               
                 1921 taaaaatctg taatacaaat ttttaaactg atgcttcatt ttgctacaaa ataatttgga 
               
               
                   
               
               
                 1981 gtaaatgttt gatatgattt atttatgaaa cctaatgaag cagaattaaa tactgtatta 
               
               
                   
               
               
                 2041 aaataagttc gctgtcttta aacaaatgga gatgactact aagtcacatt gactttaaca 
               
               
                   
               
               
                 2101 tgaggtatca ctatacctta tttgttaaaa tatatactgt atacatttta tatattttaa 
               
               
                   
               
               
                 2161 cacttaatac tatgaaaaca aataattgta aaggaatctt gtcagattac agtaagaatg 
               
               
                   
               
               
                 2221 aacatatttg tggcatcgag ttaaagttta tatttecect aaatatgctg tgattetaat 
               
               
                   
               
               
                 2281 acattegtgt aggttttcaa gtagaaataa acctegtaac aagttactga acgtttaaac 
               
               
                   
               
               
                 2341 agcctgacaa gcatgtatat atgtttaaaa ttcaataaac aaagacccag tecctaaatt 
               
               
                   
               
               
                 2401 atagaaattt aaattattct tgcatgttta tcgacatcac aacagatccc taaatcccta 
               
               
                   
               
               
                 2461 aatccctaaa gattagatac aaatttttta ccacagtato acttgtcaga atttattttt 
               
               
                   
               
               
                 2521 aaatatgatt ttttaaaact gccagtaaga aattttaaat taaacccatt tgttaaagga 
               
               
                   
               
               
                 2581 tatagtgccc aagttatatg gtgacctacc tttgtcaata cttagcatta tgtatttcaa 
               
               
                   
               
               
                 2641 attatccaat atacatgtca tatatatttt tatatgtcac atatataaaa gatatgtatg 
               
               
                   
               
               
                 2701 atctatgtga atcctaagta aatattttgt tccagaaaag tacaaaataa taaaggtaaa 
               
               
                   
               
               
                 2761 aataatctat aattttcagg accacagact aagctgtcga aattaacgct gattttttta 
               
               
                   
               
               
                 2821 gggccagaat accaaaatgg ctcctctctt cccccaaaat tggacaattt caaatgcaaa 
               
               
                   
               
               
                 2881 ataattcatt atttaatata tgagttgctt cctctatttg gtttcc. 
               
            
           
         
       
     
     The present disclosure provides an isolated oligonucleotide comprising a sense strand and an anti-sense strand, wherein: the sense strand comprises a nucleotide sequence that is substantially identical to a region comprising 19-25 nucleotides between any one of the nucleotide positions selected from: a) 52 to 93; b) 133 to 184; c) 246 to 304; d) 337 to 414; e) 433 to 503; f) 522 to 571; g) 617 to 700; h) 717 to 737; i) 836 to 905; j) 944 to 964; k) 1013 to 1093; l) 1353 to 1386; and m) 1407 to 1427, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1, and the anti-sense strand is substantially complementary to the sense strand such that the sense strand and the anti-sense strand together form a double stranded region. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% identical to a region comprising 19-25 nucleotides between any one of the nucleotide positions selected from: a) 52 to 93; b) 133 to 184; c) 246 to 304; d) 337 to 414; e) 433 to 503; f) 522 to 571; g) 617 to 700; h) 717 to 737; i) 836 to 905; j) 944 to 964; k) 1013 to 1093; and l) 1353 to 1386; and m) 1407 to 1427, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is identical to a region comprising 19-25 nucleotides between any one of the nucleotide positions selected from: a) 52 to 93; b) 133 to 184; c) 246 to 304; d) 337 to 414; e) 433 to 503; f) 522 to 571; g) 617 to 700; h) 717 to 737; i) 836 to 905; j) 944 to 964; k) 1013 to 1093; and l) 1353 to 1386; and m) 1407 to 1427, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is substantially identical to a region between any one of the nucleotide positions selected from: a) 523 to 543; b) 680 to 700; and c) 1058 to 1078, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% identical to a region between any one of the nucleotide positions selected from: a) 523 to 543; b) 680 to 700; and c) 1058 to 1078; and i) 1353 to 1386, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is identical to a region between any one of the nucleotide positions selected from: a) 523 to 543; b) 680 to 700; and c) 1058 to 1078, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is substantially identical to a region between any one of the nucleotide positions selected from: a) 522 to 542; b) 523 to 543; c) 1353 to 1373; d) 1361 to 1381; and e) 1366 to 1386, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% identical to a region between any one of the nucleotide positions selected from: a) 522 to 542; b) 523 to 543; c) 1353 to 1373; d) 1361 to 1381; and e) 1366 to 1386, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is identical to a region between any one of the nucleotide positions selected from: a) 522 to 542; b) 523 to 543; c) 1353 to 1373; d) 1361 to 1381; and e) 1366 to 1386, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is substantially identical to a region between any one of the nucleotide positions selected from: a) 52 to 93; b) 133 to 184; c) 275 to 304; d) 342 to 377; e) 453 to 503; f) 548 to 571; g) 673 to 699; h) 717 to 737; i) 836 to 905; j) 944 to 964; k) 1013 to 1093; and m) 1353 to 1427, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% identical to a region between any one of the nucleotide positions selected from: a) 52 to 93; b) 133 to 184; c) 275 to 304; d) 342 to 377; e) 453 to 503; f) 548 to 571; g) 673 to 699; h) 717 to 737; i) 836 to 905; j) 944 to 964; k) 1013 to 1093; and m) 1353 to 1427, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is identical to a region between any one of the nucleotide positions selected from: a) 52 to 93; b) 133 to 184; c) 275 to 304; d) 342 to 377; e) 453 to 503; f) 548 to 571; g) 673 to 699; h) 717 to 737; i) 836 to 905; j) 944 to 964; k) 1013 to 1093; and m) 1353 to 1427, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is substantially identical to a region between any one of the nucleotide positions selected from: a) 52 to 72; b) 56 to 76, c) 57 to 77; d) 73 to 93; e) 138 to 158; f) 144 to 164; g) 133 to 153; h) 153 to 173; i) 161 to 181; j) 164 to 184; i) 275 to 295; j) 283 to 303; k) 284 to 304; l) 342 to 362; m) 345 to 365; e) 342 to 362; f) 357 to 377; g) 472 to 492; h) 473 to 493; i) 483 to 503; j) 453 to 473; k) 467 to 487; l) 548 to 568; m) 551 to 561; n) 679 to 699; o) 673 to 693; p) 717 to 737; q) 836 to 856; r) 885 to 905; s) 944 to 964; t) 1013 to 1033; u) 1060 to 1080; v) 1061 to 1081; and w) 1073 to 1093, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% identical to a region between any one of the nucleotide positions selected from: a) 52 to 72; b) 56 to 76, c) 57 to 77; d) 73 to 93; e) 138 to 158; f) 144 to 164; g) 133 to 153; h) 153 to 173; i) 161 to 181; j) 164 to 184; i) 275 to 295; j) 283 to 303; k) 284 to 304; l) 342 to 362; m) 345 to 365; e) 342 to 362; f) 357 to 377; g) 472 to 492; h) 473 to 493; i) 483 to 503; j) 453 to 473; k) 467 to 487; l) 548 to 568; m) 551 to 561; n) 679 to 699; o) 673 to 693; p) 717 to 737; q) 836 to 856; r) 885 to 905; s) 944 to 964; t) 1013 to 1033; u) 1060 to 1080; v) 1061 to 1081; and w) 1073 to 1093, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is identical to a region between any one of the nucleotide positions selected from: a) 52 to 72; b) 56 to 76, c) 57 to 77; d) 73 to 93; e) 138 to 158; f) 144 to 164; g) 133 to 153; h) 153 to 173; i) 161 to 181; j) 164 to 184; i) 275 to 295; j) 283 to 303; k) 284 to 304; l) 342 to 362; m) 345 to 365; e) 342 to 362; f) 357 to 377; g) 472 to 492; h) 473 to 493; i) 483 to 503; j) 453 to 473; k) 467 to 487; l) 548 to 568; m) 551 to 561; n) 679 to 699; o) 673 to 693; p) 717 to 737; q) 836 to 856; r) 885 to 905; s) 944 to 964; t) 1013 to 1033; u) 1060 to 1080; v) 1061 to 1081; and w) 1073 to 1093, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a sequence that substantially identical to a region between any one of the nucleotide positions selected from: a) 54 to 74; b) 148 to 179; c) 246 to 282; d) 337 to 414; e) 433 to 495; and f) 522 to 542; g) 617 to 637; h) 838 to 858; and i) 1361 to 1381, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a sequence that is at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% identical to a region between any one of the nucleotide positions selected from: a) 54 to 74; b) 148 to 179; c) 246 to 282; d) 337 to 414; e) 433 to 495; and f) 522 to 542; g) 617 to 637; h) 838 to 858; and i) 1361 to 1381, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a sequence that is identical to a region comprising the sequence between any one of the nucleotide positions selected from: a) 54 to 74; b) 148 to 179; c) 246 to 282; d) 337 to 414; e) 433 to 495; and f) 522 to 542; g) 617 to 637; h) 838 to 858; and i) 1361 to 1381, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a sequence that is substantially identical to a region between any one of the nucleotide positions selected from: a) 54 to 74; b) 158 to 178; c) 159 to 179; d) 148 to 168; e) 246 to 266; f) 262 to 282; g) 337 to 357; h) 341 to 361; i) 382 to 402; j) 394 to 414; k) 470 to 490; l) 475 to 495; m) 433 to 453; n) 435 to 455; o) 443 to 463; and p) 617 to 637, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a sequence that is at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% identical to a region between any one of the nucleotide positions selected from: a) 54 to 74; b) 158 to 178; c) 159 to 179; d) 148 to 168; e) 246 to 266; f) 262 to 282; g) 337 to 357; h) 341 to 361; i) 382 to 402; j) 394 to 414; k) 470 to 490; l) 475 to 495; m) 433 to 453; n) 435 to 455; o) 443 to 463; and p) 617 to 637, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a sequence that is identical to a region between any one of the nucleotide positions selected from: a) 54 to 74; b) 158 to 178; c) 159 to 179; d) 148 to 168; e) 246 to 266; f) 262 to 282; g) 337 to 357; h) 341 to 361; i) 382 to 402; j) 394 to 414; k) 470 to 490; l) 475 to 495; m) 433 to 453; n) 435 to 455; o) 443 to 463; and p) 617 to 637, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     The ANGPTL-3 mRNA sequence according to SEQ ID NO: 1, as described herein, is any heterologous mRNA sequence with sufficient identity to an ANGPTL-3 according to accession no. NM_014495.4, as described herein, that allows binding to the sense strand of the oligonucleotides of the present disclosure. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the isolated oligonucleotide is capable of inducing degradation of the ANGPTL-3 mRNA. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand is a single stranded RNA molecule. In some embodiments of the isolated oligonucleotide of the present disclosure, the anti-sense strand is a single stranded RNA molecule. In some embodiments of the isolated oligonucleotide of the present disclosure, both the sense strand and the anti-sense strand are single stranded RNA molecules. 
     In some embodiments, the isolated oligonucleotide of the present disclosure is a small interfering RNA (siRNA). Accordingly, the disclosure provides siRNAs, wherein the siRNA comprises a sense region and anti-sense region complementary to the sense region that together form an RNA duplex, and wherein the sense region comprises a sequence at least 70% to 100% identical to a ANGPTL-3 mRNA sequence. 
     Definitions 
     “RNAi” or “RNA interference” refers to the process of sequence-specific post-transcriptional gene silencing, mediated by double-stranded RNA (dsRNA). Duplex RNA siRNA (small interfering RNA), miRNA (micro RNA), shRNA (short hairpin RNA), ddRNA (DNA-directed RNA), piRNA (Piwi-interacting RNA), or rasiRNA (repeat associated siRNA) and modified forms thereof are all capable of mediating RNA interference. These dsRNA molecules may be commercially available or may be designed and prepared based on known sequence information, etc. The anti-sense strand of these molecules can include RNA, DNA, PNA, or a combination thereof. These DNA/RNA chimera polynucleotide includes, but is not limited to, a double-strand polynucleotide composed of DNA and RNA that inhibits the expression of a target gene. These dsRNA molecules can also include one or more modified nucleotides, as described herein, which can be incorporated on either strand. 
     In the RNAi gene silencing or knockdown process, dsRNA comprising a first (anti-sense) strand that is complementary to a portion of a target gene and a second (sense) strand that is fully or partially complementary to the first anti-sense strand is introduced into an organism. After introduction into the organism, the target gene-specific dsRNA is processed into relatively small fragments (siRNAs) and can subsequently become distributed throughout the organism, decrease messenger RNA of target gene, leading to a phenotype that may come to closely resemble the phenotype arising from a complete or partial deletion of the target gene. 
     Certain dsRNAs in cells can undergo the action of Dicer enzyme, a ribonuclease III enzyme. Dicer can process the dsRNA into shorter pieces of dsRNA, i.e. siRNAs. RNAi also involves an endonuclease complex known as the RNA induced silencing complex (RISC). Following cleavage by Dicer, siRNAs enter the RISC complex and direct cleavage of a single stranded RNA target having a sequence complementary to the anti-sense strand of the siRNA duplex. The other strand of the siRNA is the passenger strand. Cleavage of the target RNA takes place in the middle of the region complementary to the anti-sense strand of the siRNA duplex. siRNAs can thus down regulate or knock down gene expression by mediating RNA interference in a sequence-specific manner. 
     As used herein, “target gene” or “target sequence” refers to a gene or gene sequence whose corresponding RNA is targeted for degradation through the RNAi pathway using dsRNAs or siRNAs as described herein. To target a gene, for example using an siRNA, the siRNA comprises an anti-sense region complementary to, or substantially complementary to, at least a portion of the target gene or sequence, and sense strand complementary to the anti-sense strand. Once introduced into a cell, the siRNA directs the RISC complex to cleave an RNA comprising a target sequence, thereby degrading the RNA. 
     As used herein, “oligonucleotide”, “nucleic acid,” “nucleotide sequence,” and “polynucleotide” are used interchangeably and encompass both RNA and DNA, including cDNA, genomic DNA, mRNA, synthetic (e.g., chemically synthesized) DNA or RNA and chimeras of RNA and DNA. The term polynucleotide, nucleotide sequence, or nucleic acid refers to a chain of nucleotides without regard to length of the chain. The nucleic acid can be double-stranded or single-stranded. Where single-stranded, the nucleic acid can be a sense strand or an anti-sense strand. The nucleic acid can be synthesized using oligonucleotide analogs or derivatives (e.g., inosine or phosphorothioate nucleotides). Such oligonucleotides can be used, for example, to prepare nucleic acids that have altered base-pairing abilities or increased resistance to nucleases. The present disclosure further provides a nucleic acid that is the complement (which can be either a full complement or a partial complement) of a nucleic acid, nucleotide sequence, or polynucleotide of this disclosure. When dsRNA is produced synthetically, less common bases, such as inosine, 5-methylcytosine, 6-methyladenine, hypoxanthine and others can also be used for anti-sense, dsRNA, and ribozyme pairing. Other modifications, such as modification to the phosphodiester backbone, or the 2′-fluoro, the 2′-hydroxy or 2′O-methyl in the ribose sugar group of the RNA can also be made. 
     The term “isolated” can refer to a nucleic acid, nucleotide sequence or polypeptide that is substantially free of cellular material, viral material, and/or culture medium (when produced by recombinant DNA techniques), or chemical precursors or other chemicals (when chemically synthesized). Moreover, an “isolated fragment” is a fragment of a nucleic acid, nucleotide sequence or polypeptide that is not naturally occurring as a fragment and would not be found in the natural state. “Isolated” does not mean that the preparation is technically pure (homogeneous), but it is sufficiently pure to provide the polypeptide or nucleic acid in a form in which it can be used for the intended purpose. 
     The term “region” or “fragment” is used interchangeably and as applied to an oligonucleotide. 
     The ANGPTL-3 mRNA sequence, as described herein, will be understood to mean a nucleotide sequence of reduced length relative to a reference nucleic acid or nucleotide sequence of the ANGPTL-3 mRNA sequence and comprising, consisting essentially of, and/or consisting of a nucleotide sequence of contiguous nucleotides identical or almost identical (e.g., 60%, 70%, 80%, 90%, 92%, 95%, 98% or 99% identical) to the reference nucleic acid or nucleotide sequence. Such a nucleic acid fragment according to the disclosure may be, where appropriate, included in a larger polynucleotide of which it is a constituent. In some embodiments, such fragments can comprise, consist essentially of, and/or consist of oligonucleotides having a length of at least about 8, 10, 12, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, or more consecutive nucleotides of a nucleic acid or nucleotide sequence according to the disclosure. 
     As used herein, “complementary” polynucleotides are those that are capable of base pairing according to the standard Watson-Crick complementarity rules. Specifically, purines will base pair with pyrimidines to form a combination of guanine paired with cytosine (G:C) and adenine paired with either thymine (A:T) in the case of DNA, or adenine paired with uracil (A:U) in the case of RNA. For example, the sequence “A-G-T” binds to the complementary sequence “T-C-A.” It is understood that two polynucleotides may hybridize to each other even if they are not completely complementary to each other, provided that each has at least one region that is substantially complementary to the other. 
     As used herein, the term “substantially complementary” is at least 90% (e.g., 91, 92, 93, 94, 95, 96, 97, 98 or 99%) complementary to the sense strand that is substantially identical to the nucleotide sequence within the defined regions in SEQ ID NO: 1. As used herein, the term “substantially complementary” means that two nucleic acid sequences are complementary at least at about 90%, 95% or 99% of their nucleotides. 
     In some embodiments, the two nucleic acid sequences can be complementary at least at 90%, 95%, 96%, 97%, 98%, 99% or more of their nucleotides. In some embodiments, the two nucleic acid sequences can be between 90% to 95% complementary, between 70% to 100% complementary, between 95% and 96% complementary, between 90% and 100% complementary, between 96% to 97% complementary, between 60% to 80% complementary, between 97% and 98% complementary, between 70% and 90% complementary, between 98% and 99% complementary, between 80% and 100% complementary, or between 99% and 100% complementary. 
     The term “substantially complementary” can also mean that two nucleic acid sequences, sense strand and anti-sense strand have sufficient complementarity that allows binding between the sense strand and anti-sense strand to form a double stranded region comprising of between 19-25 nucleotides in length. The term “substantially complementary” can also mean that two nucleic acid sequences can hybridize under high stringency conditions, and such conditions are well known in the art. 
     As used herein, the term “substantially identical” or “sufficient identity” used interchangeably herein, is at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% (e.g., between 70% to 805, 8-% to 90% or 90% to 95% or 95% to 99% or 99% to 100%) identical to the nucleotide sequence within the defined regions in SEQ ID NO: 1. 
     As used herein, the term “identity” means that sequences are compared with one another as follows. In order to determine the percentage identity of two nucleic acid sequences, the sequences can first be aligned with respect to one another in order subsequently to make a comparison of these sequences possible. For this e.g., gaps can be inserted into the sequence of the first nucleic acid sequence and the nucleotides can be compared with the corresponding position of the second nucleic acid sequence. If a position in the first nucleic acid sequence is occupied by the same nucleotide as is the case at a position in the second sequence, the two sequences are identical at this position. The percentage identity between two sequences is a function of the number of identical positions divided by the number of all the positions compared in the sequences investigated. 
     A “percent identity” or “% identity” as used interchangeably herein, for aligned segments of a test sequence and a reference sequence is the percent of identical components which are shared by the two aligned sequences divided by the total number of components in reference sequence segment, i.e., the entire reference sequence or a smaller defined part of the reference sequence. 
     The percentage identity of two sequences can be determined with the aid of a mathematical algorithm. A preferred, but not limiting, example of a mathematical algorithm which can be used for comparison of two sequences is the algorithm of Karlin et al. (1993), PNAS USA, 90:5873-5877. Such an algorithm is integrated in the NBLAST program, with which sequences which have a desired identity to the sequences of the present disclosure can be identified. In order to obtain a gapped alignment, as described here, the “Gapped BLAST” program can be used, as is described in Altschul et al. (1997), Nucleic Acids Res, 25:3389-3402. If BLAST and Gapped BLAST programs are used, the preset parameters of the particular program (e.g. NBLAST) can be used. The sequences can be aligned further using version 9 of GAP (global alignment program) of the “Genetic Computing Group” using the preset (BLOSUM62) matrix (values −4 to +11) with a gap open penalty of −12 (for the first zero of a gap) and a gap extension penalty of −4 (for each additional successive zero in the gap). After the alignment, the percentage identity is calculated by expressing the number of agreements as a percentage content of the nucleic acids in the sequence claimed. The methods described for determination of the percentage identity of two nucleic acid sequences can also be used correspondingly, if necessary, on the coded amino acid sequences. 
     Useful methods for determining sequence identity are also disclosed in Guide to Huge Computers (Martin J. Bishop, ed., Academic Press, San Diego (1994)), and Carillo, H., and Lipton, D., (Applied Math 48:1073(1988)). More particularly, preferred computer programs for determining sequence identity include but are not limited to the Basic Local Alignment Search Tool (BLAST) programs which are publicly available from National Center Biotechnology Information (NCBI) at the National Library of Medicine, National Institute of Health, Bethesda, Md. 20894; see BLAST Manual, Altschul et al., NCBI, NLM, NIH; (Altschul et al., J. Mol. Biol. 215:403-410 (1990)); version 2.0 or higher of BLAST programs allows the introduction of gaps (deletions and insertions) into alignments; for peptide sequence BLASTX can be used to determine sequence identity; and, for polynucleotide sequence BLASTN can be used to determine sequence identity. Percent identity can be 70% identity or greater, e.g., at least 70% identity, at least 75% identity, at least 80% identity, at least 85% identity, at least 90% identity, at least 95% identity, at least 98% identity, at least 99% identity or 100% identity. 
     As used herein, “heterologous” refers to a nucleic acid sequence that either originates from another species or is from the same species or organism but is modified from either its original form or the form primarily expressed in the cell. Thus, a nucleotide sequence derived from an organism or species different from that of the cell into which the nucleotide sequence is introduced, is heterologous with respect to that cell and the cell&#39;s descendants. In addition, a heterologous nucleotide sequence includes a nucleotide sequence derived from and inserted into the same natural, original cell type, but which is present in a non-natural state, e.g., a different copy number, and/or under the control of different regulatory sequences than that found in nature. 
     Double Stranded RNAs Targeting ANGPTL-3 
     The disclosure provides isolated oligonucleotides comprising a double stranded RNAs (dsRNAs) duplex region which target a ANGPTL-3 mRNA sequence for degradation. The double stranded RNA molecule of the disclosure may be in the form of any type of RNA interference molecule known in the art. In some embodiments, the double stranded RNA molecule is a small interfering RNA (siRNA). In other embodiments, the double stranded RNA molecule is a short hairpin RNA (shRNA) molecule. In other embodiments, the double stranded RNA molecule is a Dicer substrate that is processed in a cell to produce an siRNA. In other embodiments the double stranded RNA molecule is part of a microRNA precursor molecule. 
     In some embodiments, the dsRNA is a small interfering RNA (siRNA) which targets a ANGPTL-3 mRNA sequence for degradation. In some embodiments, the siRNA targeting ANGPTL-3 is packaged in a delivery system described herein (e.g., nanoparticle). 
     The isolated oligonucleotides of the present disclosure targeting ANGPTL-3 for degradation can comprise a sense strand at least 70% identical to any fragment of a ANGPTL-3 mRNA, for example the ANGPTL-3 mRNA of SEQ ID NO: 1. In some embodiments, the sense strand comprises or consists essentially of a sequence at least 70%, at least 80%, at least 90%, at least 95% or is 100% identical to any fragment of SEQ ID NO: 1. The siRNAs targeting ANGPTL-3 for degradation can comprise an anti-sense strand at least 70% identical to a sequence complementary to any fragment of a ANGPTL-3 mRNA, for example the ANGPTL-3 mRNA of SEQ ID NO: 1. In some embodiments, the anti-sense strand comprises or consists essentially of a sequence at least 70%, at least 80%, at least 90%, at least 95% or is 100% identical to a sequence complementary to any fragment of SEQ ID NO: 1. In some embodiments, the sense region and anti-sense regions are complementary, and base pair to form an RNA duplex structure. The fragment of the ANGPTL-3 mRNA that has percent identity to the sense region of the siRNA, and which is complementary to the anti-sense region of the siRNA, can be protein coding sequence of the mRNA, an untranslated region (UTR) of the mRNA (5′ UTR or 3′ UTR), or both. 
     In some embodiments, the isolated oligonucleotides of the present disclosure comprises a sense region and anti-sense region complementary to the sense region that together form an RNA duplex, and the sense region comprises a sequence at least 70% identical to a ANGPTL-3 mRNA sequence. In some embodiments, the sense region is identical to a ANGPTL-3 mRNA sequence. 
     As used herein, the term “sense strand” or “sense region” refers to a nucleotide sequence of an siRNA molecule that is partially or fully complementary to at least a portion of a corresponding anti-sense strand or anti-sense region of the siRNA molecule. The sense strand of an isolated oligonucleotides of the present disclosure molecule can include a nucleic acid sequence having some percentage identity with a target nucleic acid sequence such as a ANGPTL-3 mRNA sequence. In some cases, the sense region may have 100% identity, i.e. complete identity or homology, to the target nucleic acid sequence. In other cases, there may be one or more mismatches between the sense region and the target nucleic acid sequence. For example, there may be 1, 2, 3, 4, 5, 6, or 7 mismatches between the sense region and the target nucleic acid sequence. 
     As used herein, the term “anti-sense strand” or “anti-sense region” refers to a nucleotide sequence of the isolated oligonucleotides of the present disclosure, that is partially or fully complementary to at least a portion of a target nucleic acid sequence. The anti-sense strand of an isolated oligonucleotides of the present disclosure molecule can include a nucleic acid sequence that is complementary to at least a portion of a corresponding sense strand of the isolated oligonucleotides. 
     In some embodiments, the sense region comprises a sequence that is at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical or 100% identical to a sequence of SEQ ID NO: 1 or a region of SEQ ID NO: 1, as disclosed herein. In some embodiments, the sense region consists essentially of a sequence that is at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical or 100% identical to a sequence of SEQ ID NO: 1 or a region of SEQ ID NO: 1, as disclosed herein. In some embodiments, the sense region comprises a sequence that is identical to a sequence of SEQ ID NO: 1 or a region of SEQ ID NO: 1, as disclosed herein. In some embodiments, the sense region consists essentially of a sequence that is identical to a sequence of SEQ ID NO: 1 or a region of SEQ ID NO: 1, as disclosed herein. 
     In some embodiments, the sense region of the isolated oligonucleotides of the present disclosure targeting ANGPTL-3 has one or more mismatches between the sequence of the isolated oligonucleotides and the ANGPTL-3 sequence. For example, the sequence of the sense region may have 1, 2, 3, 4 or 5 mismatches between the sequence of the sense region of the isolated oligonucleotides and the ANGPTL-3 sequence. In some embodiments, the ANGPTL-3 sequence is an ANGPTL-3 3′ untranslated region sequence (3′ UTR). Without wishing to be bound by theory, it is thought that siRNAs targeting the 3′ UTR have elevated mismatch tolerance when compared to mismatches in the isolated oligonucleotides targeting coding regions of a gene. Further, the isolated oligonucleotides RNAs may be tolerant of mismatches outside the seed region. As used herein, the “seed region” of the isolated oligonucleotides refers to base pairs 2-8 of the anti-sense region of the isolated oligonucleotides, i.e., the strand of the isolated oligonucleotides that is complementary to and hybridizes to the target mRNA. 
     In some embodiments, the anti-sense region comprises a sequence that is at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% identical or 100% identical to a sequence complementary to a sequence of SEQ ID NO: 1 or a region of SEQ ID NO: 1, as disclosed herein. In some embodiments, the anti-sense region consists essentially of a sequence that is at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 97% identical, at least 99% or 100% identical to a sequence complementary to a sequence of SEQ ID NO: 1 or a region of SEQ ID NO: 1. In some embodiments, the anti-sense region comprises a sequence that is identical to a sequence complementary to a sequence of SEQ ID NO: 1 or a region of SEQ ID NO: 1. In some embodiments, the sense region consists essentially of a sequence that is complementary to a sequence of SEQ ID NO: 1 or a region of SEQ ID NO: 1. 
     The anti-sense region of the ANGPTL-3 targeting isolated oligonucleotide of the present disclosure is complementary to the sense region. In some embodiments, the sense region and the anti-sense region are fully complementary (no mismatches). In some embodiments the anti-sense region is partially complementary to the sense region, i.e., there are 1, 2, 3, 4 or 5 mismatches between the sense region and the anti-sense region. 
     In general, isolated oligonucleotide of the present disclosure comprise an RNA duplex that is about 16 to about 25 nucleotides in length. In some embodiments, the RNA duplex is between about 17 and about 24 nucleotides in length, between about 18 and about 23 nucleotides in length, or between about 19 and about 22 nucleotides in length. In some embodiments, the RNA duplex is 19 nucleotides in length. In some embodiments, the RNA duplex is 20 nucleotides in length. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand is a single stranded RNA molecule. In some embodiments of the isolated oligonucleotide of the present disclosure, the anti-sense strand is a single stranded RNA molecule. In some embodiments of the isolated oligonucleotide of the present disclosure, both the sense strand and the anti-sense strand are single stranded RNA molecules. In some embodiments of the isolated oligonucleotide of the present disclosure is an siRNA targeting ANGPTL-3, that comprises two different single stranded RNAs, the first comprising the sense region and the second comprising the anti-sense region, which hybridize to form an RNA duplex. 
     In some embodiments, the isolated oligonucleotide of the present disclosure, can have one or more overhangs from the duplex region. The overhangs, which are non-base-paired, single strand regions, can be from one to eight nucleotides in length, or longer. An overhang can be a 3′ overhang, wherein the 3′-end of a strand has a single strand region of from one to eight nucleotides. An overhang can be a 5′ overhang, wherein the 5′-end of a strand has a single strand region of from one to eight nucleotides. 
     The overhangs of the isolated oligonucleotide of the present disclosure can be the same length, or can be different lengths. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the single stranded RNA molecule of the sense strand comprises a 3′ overhang. In some embodiments, in the single stranded RNA molecule of the sense strand, the 3′ overhang comprise at least one nucleotide. In some embodiments, in the single stranded RNA molecule of the sense strand, the 3′ overhang comprise two nucleotides. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the single stranded RNA molecule of the anti-sense strand comprises a 3′ overhang. In some embodiments, in the single stranded RNA molecule of the anti-sense strand, the 3′ overhang comprise at least one nucleotide. In some embodiments, in the single stranded RNA molecule of the anti-sense strand, the 3′ overhang comprise two nucleotides. 
     In additional embodiments, both ends of isolated oligonucleotide of the present disclosure have an overhang, for example, a 3′ dinucleotide overhang on each end. The overhangs at the 5′- and 3′-ends may be of different lengths, or be the same length. 
     An overhang of an isolated oligonucleotide of the present disclosure can contain one or more deoxyribonucleotides, one or more ribonucleotides, or a combination of deoxyribonucleotides and ribonucleotides. In some embodiments, one, or both, of the overhang nucleotides of an siRNA may be 2′-deoxyribonucleotides. 
     In some embodiments, the first single stranded RNA molecule comprises a first 3′ overhang. In some embodiments, the second single stranded RNA molecule comprises a second 3′ overhang. In some embodiments, the first and second 3′ overhangs comprise a dinucleotide. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the 3′ overhang comprises any one of thymidine-thymidine (dTdT), Adenine-Adenine (AA), Cysteine-Cysteine (CC), Guanine-Guanine (GG) or Uracil-Uracil (UU). In some embodiments, the isolated oligonucleotide of the present disclosure, the 3′ overhang comprises a thymidine-thymidine (dTdT) or a Uracil-Uracil (UU) overhang. In some embodiment, the 3′ overhang comprises a Uracil-Uracil (UU) overhang. Without wishing to be bound by theory, it is thought that 3′ overhangs, such as dinucleotide overhangs, enhance siRNA mediated mRNA degradation by enhancing siRNA-RISC complex formation, and/or rate of cleavage of the target mRNA by the siRNA-RISC complex. 
     In some embodiments, the isolated oligonucleotide of the present disclosure can have one or more blunt ends, in which the duplex region ends with no overhang, and the strands are base paired to the end of the duplex region. In some embodiments, the isolated oligonucleotide of the present disclosure can have one or more blunt ends, or can have one or more overhangs, or can have a combination of a blunt end and an overhang end. For example, the 5′ end of the siRNA can be blunt and the 3′ end of the same isolated oligonucleotide comprise an overhang, or vice versa. 
     In some embodiments, both ends of the isolated oligonucleotide of the present disclosure are blunt ends. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the double stranded region comprises an anti-sense strand and a sense strand, according to any one of the pairs of anti-sense strand and sense strand sequences in Table 1, as described below. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Exemplary Sequences of the Present Application 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 SEQ 
                   
                 Guide 
                 Guide 
                 SEQ 
                   
                 Passenger 
                 Passenger 
               
               
                 ID 
                 Anti-sense strand 
                 start 
                 end 
                 ID 
                 Sense strand 
                 start 
                 end 
               
               
                 NO: 
                 (guide) sequence 
                 position 
                 position 
                 NO: 
                 (passenger) sequence 
                 position 
                 position 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 2 
                 UCAAUAAAAAGAAGGAGCUUAA 
                 58 
                 78 
                 63 
                 AAGCUCCUUCUUUUUAUUGA 
                 60 
                 78 
               
               
                   
               
               
                 3 
                 UAAAUUUUUACAUCGUCUAACA 
                 163 
                 183 
                 64 
                 UUAGACGAUGUAAAAAUUUA 
                 165 
                 183 
               
               
                   
               
               
                 4 
                 UAUAAAAAGACUGAUCAAAUAU 
                 276 
                 296 
                 65 
                 AUUUGAUCAGUCUUUUUAUA 
                 278 
                 296 
               
               
                   
               
               
                 5 
                 UGACAUAUUCUUUACCUCUUCA 
                 377 
                 397 
                 66 
                 AAGAGGUAAAGAAUAUGUCA 
                 379 
                 397 
               
               
                   
               
               
                 6 
                 UUUUAAGUGAAGUUACUUCUGG 
                 522 
                 542 
                 67 
                 AGAAGUAACUUCACUUAAAA 
                 524 
                 542 
               
               
                   
               
               
                 7 
                 UUUUUAAGUGAAGUUACUUCUG 
                 523 
                 543 
                 68 
                 GAAGUAACUUCACUUAAAAA 
                 525 
                 543 
               
               
                   
               
               
                 8 
                 UGAAGAUAGAGAAAUUUCUGUG 
                 680 
                 700 
                 69 
                 CAGAAAUUUCUCUAUCUUCA 
                 682 
                 700 
               
               
                   
               
               
                 9 
                 UGAAAAACUUGAGAGUUGCUGG 
                 838 
                 858 
                 70 
                 AGCAACUCUCAAGUUUUUCA 
                 840 
                 858 
               
               
                   
               
               
                 10 
                 UUAAUGUUUGUUGUCUUUCCAG 
                 1058 
                 1078 
                 71 
                 GGAAAGACAACAAACAUUAA 
                 1060 
                 1078 
               
               
                   
               
               
                 11 
                 UGUAUAACCUUCCAUUUUGAGA 
                 1353 
                 1373 
                 72 
                 UCAAAAUGGAAGGUUAUACA 
                 1355 
                 1373 
               
               
                   
               
               
                 12 
                 UUUUAUAGAGUAUAACCUUCCA 
                 1361 
                 1381 
                 73 
                 GAAGGUUAUACUCUAUAAAA 
                 1363 
                 1381 
               
               
                   
               
               
                 13 
                 UUUGAUUUUAUAGAGUAUAACC 
                 1366 
                 1386 
                 74 
                 UUAUACUCUAUAAAAUCAAA 
                 1368 
                 1386 
               
               
                   
               
               
                 14 
                 UAAAGAAGGAGCUUAAUUGUGA 
                 52 
                 72 
                 75 
                 ACAAUUAAGCUCCUUCUUUA 
                 54 
                 72 
               
               
                   
               
               
                 15 
                 UAUAAAAAGAAGGAGCUUAAUU 
                 56 
                 76 
                 76 
                 UUAAGCUCCUUCUUUUUAUA 
                 58 
                 76 
               
               
                   
               
               
                 16 
                 UAAUAAAAAGAAGGAGCUUAAU 
                 57 
                 77 
                 77 
                 UAAGCUCCUUCUUUUUAUUA 
                 59 
                 77 
               
               
                   
               
               
                 17 
                 UAAAUAACUAGAGGAACAAUAA 
                 73 
                 93 
                 78 
                 AUUGUUCCUCUAGUUAUUUA 
                 75 
                 93 
               
               
                   
               
               
                 18 
                 UAAAUCUUGAUUUUGGCUCUGG 
                 138 
                 158 
                 79 
                 AGAGCCAAAAUCAAGAUUUA 
                 140 
                 158 
               
               
                   
               
               
                 19 
                 UCAUAGCAAAUCUUGAUUUUGG 
                 144 
                 164 
                 80 
                 AAAAUCAAGAUUUGCUAUGA 
                 146 
                 164 
               
               
                   
               
               
                 20 
                 UUUGAUUUUGGCUCUGGAGAUA 
                 133 
                 153 
                 81 
                 UCUCCAGAGCCAAAAUCAAA 
                 135 
                 153 
               
               
                   
               
               
                 21 
                 UAUCGUCUAACAUAGCAAAUCU 
                 153 
                 173 
                 82 
                 AUUUGCUAUGUUAGACGAUA 
                 155 
                 173 
               
               
                   
               
               
                 22 
                 UAUUUUUACAUCGUCUAACAUA 
                 161 
                 181 
                 83 
                 UGUUAGACGAUGUAAAAAUA 
                 163 
                 181 
               
               
                   
               
               
                 23 
                 UAAAAUUUUUACAUCGUCUAAC 
                 164 
                 184 
                 84 
                 UAGACGAUGUAAAAAUUUUA 
                 166 
                 184 
               
               
                   
               
               
                 24 
                 UGAUAGAUCAUAAAAAGACUGA 
                 284 
                 304 
                 85 
                 AGUCUUUUUAUGAUCUAUCA 
                 286 
                 304 
               
               
                   
               
               
                 25 
                 UUAAAAAGACUGAUCAAAUAUG 
                 275 
                 295 
                 86 
                 UAUUUGAUCAGUCUUUUUAA 
                 277 
                 295 
               
               
                   
               
               
                 26 
                 UAUAGAUCAUAAAAAGACUGAU 
                 283 
                 303 
                 87 
                 CAGUCUUUUUAUGAUCUAUA 
                 285 
                 303 
               
               
                   
               
               
                 27 
                 UUAGUUUAUAUGUAGUUCUUCU 
                 345 
                 365 
                 88 
                 AAGAACUACAUAUAAACUAA 
                 347 
                 365 
               
               
                   
               
               
                 28 
                 UUUUAUAUGUAGUUCUUCUCAG 
                 342 
                 362 
                 89 
                 GAGAAGAACUACAUAUAAAA 
                 344 
                 362 
               
               
                   
               
               
                 29 
                 UAUUUUUGACUUGUAGUUUAUA 
                 357 
                 377 
                 90 
                 UAAACUACAAGUCAAAAAUA 
                 359 
                 377 
               
               
                   
               
               
                 30 
                 UUUAAGUUAGUUAGUUGCUCUU 
                 472 
                 492 
                 91 
                 GAGCAACUAACUAACUUAAA 
                 474 
                 492 
               
               
                   
               
               
                 31 
                 UAUUAAGUUAGUUAGUUGCUCU 
                 473 
                 493 
                 92 
                 AGCAACUAACUAACUUAAUA 
                 475 
                 493 
               
               
                   
               
               
                 32 
                 UUUGAUUUUGAAUUAAGUUAGU 
                 483 
                 503 
                 93 
                 UAACUUAAUUCAAAAUCAAA 
                 485 
                 503 
               
               
                   
               
               
                 33 
                 UUUCUAAAUAUUUCACUUUUUG 
                 453 
                 473 
                 94 
                 AAAAGUGAAAUAUUUAGAAA 
                 455 
                 473 
               
               
                   
               
               
                 34 
                 UUUAGUUAGUUGCUCUUCUAAA 
                 467 
                 487 
                 95 
                 UAGAAGAGCAACUAACUAAA 
                 469 
                 487 
               
               
                   
               
               
                 35 
                 UCUAUUAUCUUGUUUUUCUACA 
                 548 
                 568 
                 96 
                 UAGAAAAACAAGAUAAUAGA 
                 550 
                 568 
               
               
                   
               
               
                 36 
                 UAUGCUAUUAUCUUGUUUUUCU 
                 551 
                 571 
                 97 
                 AAAAACAAGAUAAUAGCAUA 
                 553 
                 571 
               
               
                   
               
               
                 37 
                 UAAGAUAGAGAAAUUUCUGUGG 
                 679 
                 699 
                 98 
                 ACAGAAAUUUCUCUAUCUUA 
                 681 
                 699 
               
               
                   
               
               
                 38 
                 UGAGAAAUUUCUGUGGGUUCUU 
                 673 
                 693 
                 99 
                 GAACCCACAGAAAUUUCUCA 
                 675 
                 693 
               
               
                   
               
               
                 39 
                 UCUGAAGAAAGGGAGUAGUUCU 
                 717 
                 737 
                 100 
                 AACUACUCCCUUUCUUCAGA 
                 719 
                 737 
               
               
                   
               
               
                 40 
                 UAAAACUUGAGAGUUGCUGGGU 
                 836 
                 856 
                 101 
                 CCAGCAACUCUCAAGUUUUA 
                 838 
                 856 
               
               
                   
               
               
                 41 
                 UUUGAAUUAAUGUCCAUGGACU 
                 885 
                 905 
                 102 
                 UCCAUGGACAUUAAUUCAAA 
                 887 
                 905 
               
               
                   
               
               
                 42 
                 UAAACCAUAUUUGUAGUUCUCC 
                 944 
                 964 
                 103 
                 AGAACUACAAAUAUGGUUUA 
                 946 
                 964 
               
               
                   
               
               
                 43 
                 UUAAUUAGAUUGCUUCACUAUG 
                 1013 
                 1033 
                 104 
                 UAGUGAAGCAAUCUAAUUAA 
                 1015 
                 1033 
               
               
                   
               
               
                 44 
                 UUAUAAUGUUUGUUGUCUUUCC 
                 1060 
                 1080 
                 105 
                 AAAGACAACAAACAUUAUAA 
                 1062 
                 1080 
               
               
                   
               
               
                 45 
                 UAUAUAAUGUUUGUUGUCUUUC 
                 1061 
                 1081 
                 106 
                 AAGACAACAAACAUUAUAUA 
                 1063 
                 1081 
               
               
                   
               
               
                 46 
                 UAAAGAAUAUUCAAUAUAAUGU 
                 1073 
                 1093 
                 107 
                 AUUAUAUUGAAUAUUCUUUA 
                 1075 
                 1093 
               
               
                   
               
               
                 47 
                 UAAAAAGAAGGAGCUUAAUUGU 
                 54 
                 74 
                 108 
                 AAUUAAGCUCCUUCUUUUUA 
                 56 
                 74 
               
               
                   
               
               
                 48 
                 UUUUACAUCGUCUAACAUAGCA 
                 158 
                 178 
                 109 
                 CUAUGUUAGACGAUGUAAAA 
                 160 
                 178 
               
               
                   
               
               
                 49 
                 UUUUUACAUCGUCUAACAUAGC 
                 159 
                 179 
                 110 
                 UAUGUUAGACGAUGUAAAAA 
                 161 
                 179 
               
               
                   
               
               
                 50 
                 UCUAACAUAGCAAAUCUUGAUU 
                 148 
                 168 
                 ill 
                 UCAAGAUUUGCUAUGUUAGA 
                 150 
                 168 
               
               
                   
               
               
                 51 
                 UUUGAAAUAUGUCAUUAAUUUG 
                 246 
                 266 
                 112 
                 AAUUAAUGACAUAUUUCAAA 
                 248 
                 266 
               
               
                   
               
               
                 52 
                 UCAAAUAUGUUGAGUUUUUGAA 
                 262 
                 282 
                 113 
                 CAAAAACUCAACAUAUUUGA 
                 264 
                 282 
               
               
                   
               
               
                 53 
                 UAUGUAGUUCUUCUCAGUUCCU 
                 337 
                 357 
                 114 
                 GAACUGAGAAGAACUACAUA 
                 339 
                 357 
               
               
                   
               
               
                 54 
                 UUUAUAUGUAGUUCUUCUCAGU 
                 341 
                 361 
                 115 
                 UGAGAAGAACUACAUAUAAA 
                 343 
                 361 
               
               
                   
               
               
                 55 
                 UCAAGUGACAUAUUCUUUACCU 
                 382 
                 402 
                 116 
                 GUAAAGAAUAUGUCACUUGA 
                 384 
                 402 
               
               
                   
               
               
                 56 
                 UUUGAGUUGAGUUCAAGUGACA 
                 394 
                 414 
                 117 
                 UCACUUGAACUCAACUCAAA 
                 396 
                 414 
               
               
                   
               
               
                 57 
                 UAAGUUAGUUAGUUGCUCUUCU 
                 470 
                 490 
                 118 
                 AAGAGCAACUAACUAACUUA 
                 472 
                 490 
               
               
                   
               
               
                 58 
                 UGAAUUAAGUUAGUUAGUUGCU 
                 475 
                 495 
                 119 
                 CAACUAACUAACUUAAUUCA 
                 477 
                 495 
               
               
                   
               
               
                 59 
                 UGUUGAAGUAGAAUUUUUUCUU 
                 433 
                 453 
                 120 
                 GAAAAAAUUCUACUUCAACA 
                 435 
                 453 
               
               
                   
               
               
                 60 
                 UUUGUUGAAGUAGAAUUUUUUC 
                 435 
                 455 
                 121 
                 AAAAAUUCUACUUCAACAAA 
                 437 
                 455 
               
               
                   
               
               
                 61 
                 UUUCACUUUUUGUUGAAGUAGA 
                 443 
                 463 
                 122 
                 UACUUCAACAAAAAGUGAAA 
                 445 
                 463 
               
               
                   
               
               
                 62 
                 UUUUAUUUGACUAUGCUGUUGG 
                 617 
                 637 
                 123 
                 AACAGCAUAGUCAAAUAAAA 
                 619 
                 637 
               
               
                   
               
               
                 200 
                 UUUCAAAGCUUUCUGAAUCUGU 
                 1407 
                 1427 
                 235 
                 AGAUUCAGAAAGCUUUGAAA 
                 1409 
                 1427 
               
               
                   
               
            
           
         
       
     
     In some embodiments, the sense region comprises a sequence selected from any one of the group of sense strand/passenger strand sequences listed in Table 1 or Table 2. In some embodiments, the anti-sense region comprises a sequence selected from any one of the group of anti-sense strand/guide strand sequences listed in Table 1 or Table 2. In some embodiments, the sense and anti-sense regions comprise complementary sequences selected from the group listed in Table 1 and Table 2. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the anti-sense strand comprises a nucleotide sequence according to any one of: SEQ ID NOs: 2-62 and 200. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence according to any one of: SEQ ID NOs: 63-123 and 235. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the anti-sense strand comprises a nucleotide sequence according to any one of: SEQ ID NOs: 2-62 and 200; and the sense strand comprises a nucleotide sequence according to any one of: SEQ ID NOs: 63-123 and 235, wherein the anti-sense strand and the sense strand sequences have sufficient complementarity to allow formation of a double stranded region between the anti-sense and the sense strand. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, wherein the sense strand comprises a nucleotide sequence that is identical to a region between any one of the nucleotide positions selected from: a) 523 to 543; b) 680 to 700; and c) 1058 to 1078, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1, the double stranded region comprises any one of: i) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 7 (5′ UUUUUAAGUGAAGUUACUUCUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 68 (5′ GAAGUAACUUCACUUAAAAA 3′); ii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 8 (5′ UGAAGAUAGAGAAAUUUCUGUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 69 (5′ CAGAAAUUUCUCUAUCUUCA 3′); or iii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 10 (5′ UUAAUGUUUGUUGUCUUUCCAG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 71 (5′ GGAAAGACAACAAACAUUAA 3′). 
     In some embodiments of the isolated oligonucleotide of the present disclosure, wherein the sense strand comprises a nucleotide sequence that is identical to a region between any one of the nucleotide positions selected from: a) 52 to 93; b) 133 to 184; c) 275 to 304; d) 342 to 377; e) 453 to 503; f) 548 to 571; g) 673 to 699; h) 717 to 737; i) 836 to 905; j) 944 to 964; k) 1013 to 1093; and m) 1353 to 1427, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1, the double stranded region comprises any one of: i) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 2 (5′ UCAAUAAAAAGAAGGAGCUUAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 63 (5′ AAGCUCCUUCUUUUUAUUGA 3′); ii) an anti-sense of nucleotide sequence according to SEQ ID NO: 3 (5′ UAAAUUUUUACAUCGUCUAACA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 64 (5′ UUAGACGAUGUAAAAAUUUA 3′); iii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 4 (5′ UAUAAAAAGACUGAUCAAAUAU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 65 (5′ AUUUGAUCAGUCUUUUUAUA 3′); iv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 11 (5′ UGUAUAACCUUCCAUUUUGAGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 72 (5′ UCAAAAUGGAAGGUUAUACA 3′); v) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 13 (5′ UUUGAUUUUAUAGAGUAUAACC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 74 (5′ UUAUACUCUAUAAAAUCAAA 3′); vi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 14 (5′ UAAAGAAGGAGCUUAAUUGUGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 75 (5′ ACAAUUAAGCUCCUUCUUUA 3′); vii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 15 (5′ UAUAAAAAGAAGGAGCUUAAUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 76 (5′ UUAAGCUCCUUCUUUUUAUA 3′); viii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 16 (5′ UAAUAAAAAGAAGGAGCUUAAU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 77 (5′ UAAGCUCCUUCUUUUUAUUA 3′); ix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 17 (5′ UAAAUAACUAGAGGAACAAUAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 78 (5′ AUUGUUCCUCUAGUUAUUUA 3′); x) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 18 (5′ UAAAUCUUGAUUUUGGCUCUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 79 (5′ AGAGCCAAAAUCAAGAUUUA 3′); xi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 19 (5′ UCAUAGCAAAUCUUGAUUUUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 80 (5′ AAAAUCAAGAUUUGCUAUGA 3′); xii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 20 (5′ UUUGAUUUUGGCUCUGGAGAUA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 81 (5′ UCUCCAGAGCCAAAAUCAAA 3′); xiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 21 (5′ UAUCGUCUAACAUAGCAAAUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 82 (5′ AUUUGCUAUGUUAGACGAUA 3′); xiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 22 (5′ UAUUUUUACAUCGUCUAACAUA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 83 (5′ UGUUAGACGAUGUAAAAAUA 3′); xv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 23 (5′ UAAAAUUUUUACAUCGUCUAAC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 84 (5′ UAGACGAUGUAAAAAUUUUA 3′); xvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 24 (5′ UGAUAGAUCAUAAAAAGACUGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 85 (5′ AGUCUUUUUAUGAUCUAUCA 3′); xvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 25 (5′ UUAAAAAGACUGAUCAAAUAUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 86 (5′ UAUUUGAUCAGUCUUUUUAA 3′); xviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 26 (5′ UAUAGAUCAUAAAAAGACUGAU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 87 (5′ CAGUCUUUUUAUGAUCUAUA 3′); xix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 27 (5′ UUAGUUUAUAUGUAGUUCUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 88 (5′ AAGAACUACAUAUAAACUAA 3′); xx) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 28 (5′ UUUUAUAUGUAGUUCUUCUCAG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 89 (5′ GAGAAGAACUACAUAUAAAA 3′); xxi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 29 (5′ UAUUUUUGACUUGUAGUUUAUA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 90 (5′ UAAACUACAAGUCAAAAAUA 3′); xxii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 30 (5′ UUUAAGUUAGUUAGUUGCUCUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 91 (5′ GAGCAACUAACUAACUUAAA 3′); xxiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 31 (5′ UAUUAAGUUAGUUAGUUGCUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 92 (5′ AGCAACUAACUAACUUAAUA 3′); xxiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 32 (5′ UUUGAUUUUGAAUUAAGUUAGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 93 (5′ UAACUUAAUUCAAAAUCAAA 3′); xxv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 33 (5′ UUUCUAAAUAUUUCACUUUUUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 94 (5′ AAAAGUGAAAUAUUUAGAAA 3′); xxvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 34 (5′ UUUAGUUAGUUGCUCUUCUAAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 95 (5′ UAGAAGAGCAACUAACUAAA 3′); xxvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 35 (5′ UCUAUUAUCUUGUUUUUCUACA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 96 (5′ UAGAAAAACAAGAUAAUAGA 3′); xxviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 36 (5′ UAUGCUAUUAUCUUGUUUUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 97 (5′ AAAAACAAGAUAAUAGCAUA 3′); xxix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 37 (5′ UAAGAUAGAGAAAUUUCUGUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 98 (5′ ACAGAAAUUUCUCUAUCUUA 3′); xxx) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 38 (5′ UGAGAAAUUUCUGUGGGUUCUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 99 (5′ GAACCCACAGAAAUUUCUCA 3′); xxxi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 39 (5′ UCUGAAGAAAGGGAGUAGUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 100 (5′ AACUACUCCCUUUCUUCAGA 3′); xxxii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 40 (5′ UAAAACUUGAGAGUUGCUGGGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 101 (5′ CCAGCAACUCUCAAGUUUUA 3′); xxxiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 41 (5′ UUUGAAUUAAUGUCCAUGGACU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 102 (5′ UCCAUGGACAUUAAUUCAAA 3′); xxxiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 42 (5′ UAAACCAUAUUUGUAGUUCUCC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 103 (5′ AGAACUACAAAUAUGGUUUA 3′); xxxv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 43 (5′ UUAAUUAGAUUGCUUCACUAUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 104 (5′ UAGUGAAGCAAUCUAAUUAA 3′); xxxvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 44 (5′ UUAUAAUGUUUGUUGUCUUUCC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 105 (5′ AAAGACAACAAACAUUAUAA 3′); xxxvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 45 (5′ UAUAUAAUGUUUGUUGUCUUUC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 106 (5′ AAGACAACAAACAUUAUAUA 3′); xxxviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 46 (5′ UAAAGAAUAUUCAAUAUAAUGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 107 (5′ AUUAUAUUGAAUAUUCUUUA 3′); or xxxix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 200 (5′ UUUCAAAGCUUUCUGAAUCUGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 235 (5′ AGAUUCAGAAAGCUUUGAAA 3′). 
     In some embodiments of the isolated oligonucleotide of the present disclosure, wherein the sense strand comprises a sequence that is identical to a region between any one of the nucleotide positions selected from: a) 54 to 74; b) 148 to 179; c) 246 to 282; d) 337 to 414; e) 433 to 495; and f) 522 to 542; g) 617 to 637; h) 838 to 858; and i) 1361 to 1381, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1, the double stranded region comprises any one of: i) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 5 (5′ UGACAUAUUCUUUACCUCUUCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 66 (5′ AAGAGGUAAAGAAUAUGUCA 3′); ii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 6 (5′ UUUUAAGUGAAGUUACUUCUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 67 (5′ AGAAGUAACUUCACUUAAAA 3′); iii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 9 (5′ UGAAAAACUUGAGAGUUGCUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 70 (5′ AGCAACUCUCAAGUUUUUCA 3′); iv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 12 (5′ UUUUAUAGAGUAUAACCUUCCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 73 (5′ GAAGGUUAUACUCUAUAAAA 3′); v) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 47 (5′ UAAAAAGAAGGAGCUUAAUUGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 108 (5′ AAUUAAGCUCCUUCUUUUUA 3′); vi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 48 (5′ UUUUACAUCGUCUAACAUAGCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 109 (5′ CUAUGUUAGACGAUGUAAAA 3′); vii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 49 (5′ UUUUUACAUCGUCUAACAUAGC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 110 (5′ UAUGUUAGACGAUGUAAAAA 3′); viii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 50 (5′ UCUAACAUAGCAAAUCUUGAUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 111 (5′ UCAAGAUUUGCUAUGUUAGA 3′); ix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 51 (5′ UUUGAAAUAUGUCAUUAAUUUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 112 (5′ AAUUAAUGACAUAUUUCAAA 3′); x) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 52 (5′ UCAAAUAUGUUGAGUUUUUGAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 113 (5′ CAAAAACUCAACAUAUUUGA 3′); xi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 53 (5′ UAUGUAGUUCUUCUCAGUUCCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 114 (5′ GAACUGAGAAGAACUACAUA 3′); xii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 54 (5′ UUUAUAUGUAGUUCUUCUCAGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 115 (5′ UGAGAAGAACUACAUAUAAA 3′); xiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 55 (5′ UCAAGUGACAUAUUCUUUACCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 116 (5′ GUAAAGAAUAUGUCACUUGA 3′); xiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 56 (5′ UUUGAGUUGAGUUCAAGUGACA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 117 (5′ UCACUUGAACUCAACUCAAA 3′); xv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 57 (5′ UAAGUUAGUUAGUUGCUCUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 118 (5′ AAGAGCAACUAACUAACUUA 3′); xvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 58 (5′ UGAAUUAAGUUAGUUAGUUGCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 119 (5′ CAACUAACUAACUUAAUUCA 3′); xvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 59 (5′ UGUUGAAGUAGAAUUUUUUCUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 120 (5′ GAAAAAAUUCUACUUCAACA 3′); xviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 60 (5′ UUUGUUGAAGUAGAAUUUUUUC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 121 (5′ AAAAAUUCUACUUCAACAAA 3′); xix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 61 (5′ UUUCACUUUUUGUUGAAGUAGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 122 (5′ UACUUCAACAAAAAGUGAAA 3′); or xx) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 62 (5′ UUUUAUUUGACUAUGCUGUUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 123 (5′ AACAGCAUAGUCAAAUAAAA 3′). 
     In some embodiments, the isolated oligonucleotide of the present disclosure attenuates expression of the ANGPTL-3 mRNA by 20% to 50%, at a dose of 0.02 nM. 
     In some embodiments of the isolated oligonucleotide of the present disclosure that attenuate expression of the ANGPTL-3 mRNA by 20% to 50%, at a dose of 0.02 nM, the double stranded region comprises any one of: i) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 3 (5′ UAAAUUUUUACAUCGUCUAACA), and a sense strand of nucleotide sequence according to SEQ ID NO: 64 (5′ UUAGACGAUGUAAAAAUUUA 3′); ii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 4 (5′ UAUAAAAAGACUGAUCAAAUAU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 65 (5′ AUUUGAUCAGUCUUUUUAUA 3′); iii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 7 (5′ UUUUUAAGUGAAGUUACUUCUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 68 (5′ GAAGUAACUUCACUUAAAAA 3′); iv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 8 (5′ UGAAGAUAGAGAAAUUUCUGUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 69 (5′ CAGAAAUUUCUCUAUCUUCA 3′); v) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 9 (5′ UGAAAAACUUGAGAGUUGCUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 70 (5′ AGCAACUCUCAAGUUUUUCA 3′); vi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 10 (5′ UUAAUGUUUGUUGUCUUUCCAG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 71 (5′ GGAAAGACAACAAACAUUAA 3′); vii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 12 (5′ UUUUAUAGAGUAUAACCUUCCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 73 (5′ GAAGGUUAUACUCUAUAAAA 3′), viii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 14 (5′ UAAAGAAGGAGCUUAAUUGUGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 75 (5′ ACAAUUAAGCUCCUUCUUUA 3′); ix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 16 (5′ UAAUAAAAAGAAGGAGCUUAAU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 77 (5′ UAAGCUCCUUCUUUUUAUUA 3′); x) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 17 (5′ UAAAUAACUAGAGGAACAAUAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 78 (5′ AUUGUUCCUCUAGUUAUUUA 3′); xi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 20 (5′ UUUGAUUUUGGCUCUGGAGAUA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 81 (5′ UCUCCAGAGCCAAAAUCAAA 3′), xii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 21 (5′ UAUCGUCUAACAUAGCAAAUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 82 (5′ AUUUGCUAUGUUAGACGAUA 3′); xiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 24 (5′ UGAUAGAUCAUAAAAAGACUGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 85 (5′ AGUCUUUUUAUGAUCUAUCA 3′); xiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 25 (5′ UUAAAAAGACUGAUCAAAUAUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 86 (5′ UAUUUGAUCAGUCUUUUUAA 3′); xv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 26 (5′ UAUAGAUCAUAAAAAGACUGAU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 87 (5′ CAGUCUUUUUAUGAUCUAUA 3′); xvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 27 (5′ UUAGUUUAUAUGUAGUUCUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 88 (5′ AAGAACUACAUAUAAACUAA 3′); xvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 30 (5′ UUUAAGUUAGUUAGUUGCUCUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 91 (5′ GAGCAACUAACUAACUUAAA 3′); xiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 32 (5′ UUUGAUUUUGAAUUAAGUUAGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 93 (5′ UAACUUAAUUCAAAAUCAAA 3′); xix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 33 (5′ UUUCUAAAUAUUUCACUUUUUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 94 (5′ AAAAGUGAAAUAUUUAGAAA 3′); xx) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 35 (5′ UCUAUUAUCUUGUUUUUCUACA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 96 (5′ UAGAAAAACAAGAUAAUAGA 3′); xxi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 37 (5′ UAAGAUAGAGAAAUUUCUGUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 98 (5′ ACAGAAAUUUCUCUAUCUUA 3′); xxii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 38 (5′ UGAGAAAUUUCUGUGGGUUCUU 3′), and an sense strand of nucleotide sequence according to SEQ ID NO: 99 (5′ GAACCCACAGAAAUUUCUCA 3′); xxiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 39 (5′ UCUGAAGAAAGGGAGUAGUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 100 (5′ AACUACUCCCUUUCUUCAGA 3′); xxiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 40 (5′ UAAAACUUGAGAGUUGCUGGGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 101 (5′ CCAGCAACUCUCAAGUUUUA 3′); xxv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 41 (5′ UUUGAAUUAAUGUCCAUGGACU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 102 (5′ UCCAUGGACAUUAAUUCAAA 3′); xxvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 42 (5′ UAAACCAUAUUUGUAGUUCUCC 3′), and an anti-sense strand of nucleotide sequence according to SEQ ID NO: 103 (5′ AGAACUACAAAUAUGGUUUA 3′); xxvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 5 (5′ UGACAUAUUCUUUACCUCUUCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 66 (5′ AAGAGGUAAAGAAUAUGUCA 3′); xxviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 44 (5′ UUAUAAUGUUUGUUGUCUUUCC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 105 (5′ AAAGACAACAAACAUUAUAA 3′); xxix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 47 (5′ UAAAAAGAAGGAGCUUAAUUGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 108 (5′ AAUUAAGCUCCUUCUUUUUA 3′); xxx) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 48 (5′ UUUUACAUCGUCUAACAUAGCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 109 (5′ CUAUGUUAGACGAUGUAAAA 3′); xxxi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 49 (5′ UUUUUACAUCGUCUAACAUAGC 3′), and an anti-sense strand of nucleotide sequence according to SEQ ID NO: 110 (5′ UAUGUUAGACGAUGUAAAAA 3′); xxxii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 50 (5′ UCUAACAUAGCAAAUCUUGAUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 111 (5′ UCAAGAUUUGCUAUGUUAGA 3′); xxxiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 51 (5′ UUUGAAAUAUGUCAUUAAUUUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 112 (5′ AAUUAAUGACAUAUUUCAAA 3′); xxxiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 52 (5′ UCAAAUAUGUUGAGUUUUUGAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 113 (5′ CAAAAACUCAACAUAUUUGA 3′); xxxv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 53 (5′ UAUGUAGUUCUUCUCAGUUCCU 3′), and an anti-sense strand of nucleotide sequence according to SEQ ID NO: 114 (5′ GAACUGAGAAGAACUACAUA 3′); xxxvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 54 (5′ UUUAUAUGUAGUUCUUCUCAGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 115 (5′ UGAGAAGAACUACAUAUAAA 3′); xxxvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 55 (5′ UCAAGUGACAUAUUCUUUACCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 116 (5′ GUAAAGAAUAUGUCACUUGA 3′); xxxviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 56 (5′ UUUGAGUUGAGUUCAAGUGACA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 117 (5′ UCACUUGAACUCAACUCAAA 3′); xxxix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 58 (5′ UGAAUUAAGUUAGUUAGUUGCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 119 (5′ CAACUAACUAACUUAAUUCA 3′); xL) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 59 (5′ UGUUGAAGUAGAAUUUUUUCUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 120 (5′ GAAAAAAUUCUACUUCAACA 3′); xLi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 60 (5′ UUUGUUGAAGUAGAAUUUUUUC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 121 (5′ AAAAAUUCUACUUCAACAAA 3′); xLii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 61 (5′ UUUCACUUUUUGUUGAAGUAGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 122 (5′ UACUUCAACAAAAAGUGAAA 3′); xLiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 62 (5′ UUUUAUUUGACUAUGCUGUUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 123 (5′ AACAGCAUAGUCAAAUAAAA 3′); xLiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 28 (5′ UUUUAUAUGUAGUUCUUCUCAG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 89 (5′ GAGAAGAACUACAUAUAAAA 3′); or xLv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 200 (5′ UUUCAAAGCUUUCUGAAUCUGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 235 (5′ AGAUUCAGAAAGCUUUGAAA 3′). 
     In some embodiments, the isolated oligonucleotide of the present disclosure attenuates expression of the ANGPTL-3 mRNA by at least 50%, at a dose of 0.02 nM. 
     In some embodiments of the isolated oligonucleotide of the present disclosure that attenuate expression of the ANGPTL-3 mRNA by at least 50%, at a dose of 0.02 nM, the double stranded region comprises any one of: i) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 2 (5′ UCAAUAAAAAGAAGGAGCUUAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 63 (5′ AAGCUCCUUCUUUUUAUUGA 3′); ii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 6 (5′ UUUUAAGUGAAGUUACUUCUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 67 (5′ AGAAGUAACUUCACUUAAAA 3′); iii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 11 (5′ UGUAUAACCUUCCAUUUUGAGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 72 (5′ UCAAAAUGGAAGGUUAUACA 3′), iv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 13 (5′ UUUGAUUUUAUAGAGUAUAACC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 74 (5′ UUAUACUCUAUAAAAUCAAA 3′); v) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 15 (5′ UAUAAAAAGAAGGAGCUUAAUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 76 (5′ UUAAGCUCCUUCUUUUUAUA 3′); vi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 18 (5′ UAAAUCUUGAUUUUGGCUCUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 79 (5′ AGAGCCAAAAUCAAGAUUUA 3′); vii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 19 (5′ UCAUAGCAAAUCUUGAUUUUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 80 (5′ AAAAUCAAGAUUUGCUAUGA 3′); viii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 22 (5′ UAUUUUUACAUCGUCUAACAUA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 83 (5′ UGUUAGACGAUGUAAAAAUA 3′); ix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 23 (5′ UAAAAUUUUUACAUCGUCUAAC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 84 (5′ UAGACGAUGUAAAAAUUUUA 3′); x) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 29 (5′ UAUUUUUGACUUGUAGUUUAUA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 90 (5′ UAAACUACAAGUCAAAAAUA 3′); xi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 31 (5′ UAUUAAGUUAGUUAGUUGCUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 92 (5′ AGCAACUAACUAACUUAAUA 3′); xii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 34 (5′ UUUAGUUAGUUGCUCUUCUAAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 95 (5′ UAGAAGAGCAACUAACUAAA 3′); xiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 36 (5′ UAUGCUAUUAUCUUGUUUUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 97 (5′ AAAAACAAGAUAAUAGCAUA 3′); xiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 45 (5′ UAUAUAAUGUUUGUUGUCUUUC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 106 (5′ AAGACAACAAACAUUAUAUA 3′); xv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 57 (5′ UAAGUUAGUUAGUUGCUCUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 118 (5′ AAGAGCAACUAACUAACUUA 3′); or xvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 46 (5′ UAAAGAAUAUUCAAUAUAAUGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 107 (5′ AUUAUAUUGAAUAUUCUUUA 3′). 
     In some embodiments, the isolated oligonucleotide of the present disclosure attenuates expression of the ANGPTL-3 mRNA by 50% to 75%, at a dose of 0.1 nM. 
     In some embodiments of the isolated oligonucleotide of the present disclosure that attenuate expression of the ANGPTL-3 mRNA by 50% to 75%, at a dose of 0.1 nM, the double stranded region comprises any one of: i) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 4 (5′ UAUAAAAAGACUGAUCAAAUAU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 65 (5′ AUUUGAUCAGUCUUUUUAUA 3′); ii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 10 (5′ UUAAUGUUUGUUGUCUUUCCAG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 71 (5′ GGAAAGACAACAAACAUUAA 3′); iii) anti-sense strand of nucleotide sequence according to SEQ ID NO: 12 (5′ UUUUAUAGAGUAUAACCUUCCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 73 (5′ GAAGGUUAUACUCUAUAAAA 3′); iv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 16 (5′ UAAUAAAAAGAAGGAGCUUAAU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 77 (5′ UAAGCUCCUUCUUUUUAUUA 3′); v) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 24 (5′ UGAUAGAUCAUAAAAAGACUGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 85 (5′ AGUCUUUUUAUGAUCUAUCA 3′); vi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 27 (5′ UUAGUUUAUAUGUAGUUCUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 88 (5′ AAGAACUACAUAUAAACUAA 3′); vii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 30 (5′ UUUAAGUUAGUUAGUUGCUCUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 91 (5′ GAGCAACUAACUAACUUAAA 3′); viii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 32 (5′ UUUGAUUUUGAAUUAAGUUAGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 93 (5′ UAACUUAAUUCAAAAUCAAA 3′); ix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 35 (5′ UCUAUUAUCUUGUUUUUCUACA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 96 (5′ UAGAAAAACAAGAUAAUAGA 3′); x) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 37 (5′ UAAGAUAGAGAAAUUUCUGUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 98 (5′ ACAGAAAUUUCUCUAUCUUA 3′); xi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 38 (5′ UGAGAAAUUUCUGUGGGUUCUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 99 (5′ GAACCCACAGAAAUUUCUCA 3′); xii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 39 (5′ UCUGAAGAAAGGGAGUAGUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 100 (5′ AACUACUCCCUUUCUUCAGA 3′); xiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 41 (5′ UUUGAAUUAAUGUCCAUGGACU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 102 (5′ UCCAUGGACAUUAAUUCAAA 3′); xiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 42 (5′ UAAACCAUAUUUGUAGUUCUCC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 103 (5′ AGAACUACAAAUAUGGUUUA 3′); xv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 44 (5′ UUAUAAUGUUUGUUGUCUUUCC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 105 (5′ AAAGACAACAAACAUUAUAA 3′); xvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 46 (5′ UAAAGAAUAUUCAAUAUAAUGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 107 (5′ AUUAUAUUGAAUAUUCUUUA 3′); xvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 48 (5′ UUUUACAUCGUCUAACAUAGCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 109 (5′ CUAUGUUAGACGAUGUAAAA 3′); xviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 49 (5′ UUUUUACAUCGUCUAACAUAGC 3′), and an anti-sense strand of nucleotide sequence according to SEQ ID NO: 110 (5′ UAUGUUAGACGAUGUAAAAA 3′); xix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 52 (5′ UCAAAUAUGUUGAGUUUUUGAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 113 (5′ CAAAAACUCAACAUAUUUGA 3′); xx) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 53 (5′ UAUGUAGUUCUUCUCAGUUCCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 114 (5′ GAACUGAGAAGAACUACAUA 3′); xxi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 56 (5′ UUUGAGUUGAGUUCAAGUGACA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 117 (5′ UCACUUGAACUCAACUCAAA 3′); xxii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 60 (5′ UUUGUUGAAGUAGAAUUUUUUC 3′), and an anti-sense strand of nucleotide sequence according to SEQ ID NO: 121 (5′ AAAAAUUCUACUUCAACAAA 3′); xxiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 61 (5′ UUUCACUUUUUGUUGAAGUAGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 122 (5′ UACUUCAACAAAAAGUGAAA 3′); xxiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 19 (5′ UCAUAGCAAAUCUUGAUUUUGG 3′), and an anti-sense strand of nucleotide sequence according to SEQ ID NO: 80 (5′ AAAAUCAAGAUUUGCUAUGA 3′); or xxv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 58 (5′ UGAAUUAAGUUAGUUAGUUGCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 119 (5′ CAACUAACUAACUUAAUUCA 3′). 
     In some embodiments, the isolated oligonucleotide of the present disclosure attenuates expression of the ANGPTL-3 mRNA by at least 75%, at a dose of 0.1 nM. 
     In some embodiments of the isolated oligonucleotide of the present disclosure that attenuates expression of the ANGPTL-3 mRNA by at least 75%, at a dose of 0.1 nM, the double stranded region comprises any one of: i) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 2 (5′ UCAAUAAAAAGAAGGAGCUUAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 63 (5′ AAGCUCCUUCUUUUUAUUGA 3′); ii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 3 (5′ UAAAUUUUUACAUCGUCUAACA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 64 (5′ UUAGACGAUGUAAAAAUUUA 3′); iii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 6 (5′ UUUUAAGUGAAGUUACUUCUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 67 (5′ AGAAGUAACUUCACUUAAAA 3′); iv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 8 (5′ UGAAGAUAGAGAAAUUUCUGUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 69 (5′ CAGAAAUUUCUCUAUCUUCA 3′); v) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 9 (5′ UGAAAAACUUGAGAGUUGCUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 70 (5′ AGCAACUCUCAAGUUUUUCA 3′); vi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 11 (5′ UGUAUAACCUUCCAUUUUGAGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 72 (5′ UCAAAAUGGAAGGUUAUACA 3′); vii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 13 (5′ UUUGAUUUUAUAGAGUAUAACC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 74 (5′ UUAUACUCUAUAAAAUCAAA 3′); viii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 14 (5′ UAAAGAAGGAGCUUAAUUGUGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 75 (5′ ACAAUUAAGCUCCUUCUUUA 3′); ix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 15 (5′ UAUAAAAAGAAGGAGCUUAAUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 76 (5′ UUAAGCUCCUUCUUUUUAUA 3′); x) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 17 (5′ UAAAUAACUAGAGGAACAAUAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 78 (5′ AUUGUUCCUCUAGUUAUUUA 3′); xi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 18 (5′ UAAAUCUUGAUUUUGGCUCUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 79 (5′ AGAGCCAAAAUCAAGAUUUA 3′); xii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 20 (5′ UUUGAUUUUGGCUCUGGAGAUA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 81 (5′ UCUCCAGAGCCAAAAUCAAA 3′); xiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 21 (5′ UAUCGUCUAACAUAGCAAAUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 82 (5′ AUUUGCUAUGUUAGACGAUA 3′); xiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 22 (5′ UAUUUUUACAUCGUCUAACAUA 3′), and an anti-sense strand of nucleotide sequence according to SEQ ID NO: 83 (5′ UGUUAGACGAUGUAAAAAUA 3′); xv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 23 (5′ UAAAAUUUUUACAUCGUCUAAC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 84 (5′ UAGACGAUGUAAAAAUUUUA 3′); xvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 25 (5′ UUAAAAAGACUGAUCAAAUAUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 86 (5′ UAUUUGAUCAGUCUUUUUAA 3′), xvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 26 (5′ UAUAGAUCAUAAAAAGACUGAU 3′), and an anti-sense strand of nucleotide sequence according to SEQ ID NO: 87 (5′ CAGUCUUUUUAUGAUCUAUA 3′); xviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 29 (5′ UAUUUUUGACUUGUAGUUUAUA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 90 (5′ UAAACUACAAGUCAAAAAUA 3′); xix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 31 (5′ UAUUAAGUUAGUUAGUUGCUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 92 (5′ AGCAACUAACUAACUUAAUA 3′); xx) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 33 (5′ UUUCUAAAUAUUUCACUUUUUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 94 (5′ AAAAGUGAAAUAUUUAGAAA 3′); xxi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 34 (5′ UUUAGUUAGUUGCUCUUCUAAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 95 (5′ UAGAAGAGCAACUAACUAAA 3′); xxii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 36 (5′ UAUGCUAUUAUCUUGUUUUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 97 (5′ AAAAACAAGAUAAUAGCAUA 3′); xxiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 40 (5′ UAAAACUUGAGAGUUGCUGGGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 101 (5′ CCAGCAACUCUCAAGUUUUA 3′); xxiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 43 (5′ UUAAUUAGAUUGCUUCACUAUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 104 (5′ UAGUGAAGCAAUCUAAUUAA 3′); xxv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 45 (5′ UAUAUAAUGUUUGUUGUCUUUC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 106 (5′ AAGACAACAAACAUUAUAUA 3′); xxvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 47 (5′ UAAAAAGAAGGAGCUUAAUUGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 108 (5′ AAUUAAGCUCCUUCUUUUUA 3′); xxvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 50 (5′ UCUAACAUAGCAAAUCUUGAUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 111 (5′ UCAAGAUUUGCUAUGUUAGA 3′); xxviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 51 (5′ UUUGAAAUAUGUCAUUAAUUUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 112 (5′ AAUUAAUGACAUAUUUCAAA 3′); xxix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 54 (5′ UUUAUAUGUAGUUCUUCUCAGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 115 (5′ UGAGAAGAACUACAUAUAAA 3′); xxx) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 55 (5′ UCAAGUGACAUAUUCUUUACCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 116 (5′ GUAAAGAAUAUGUCACUUGA 3′); xxxi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 57 (5′ UAAGUUAGUUAGUUGCUCUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 118 (5′ AAGAGCAACUAACUAACUUA 3′); xxxii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 5 (5′ UGACAUAUUCUUUACCUCUUCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 66 (5′ AAGAGGUAAAGAAUAUGUCA 3′); xxxiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 59 (5′ UGUUGAAGUAGAAUUUUUUCUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 120 (5′ GAAAAAAUUCUACUUCAACA 3′); xxxiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 62 (5′ UUUUAUUUGACUAUGCUGUUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 123 (5′ AACAGCAUAGUCAAAUAAAA 3′); xxxv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 7 (5′ UUUUUAAGUGAAGUUACUUCUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 68 (5′ GAAGUAACUUCACUUAAAAA3′); xxxvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 28 (5′ UUUUAUAUGUAGUUCUUCUCAG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 89 (5′ GAGAAGAACUACAUAUAAAA 3′); or xxxvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 200 (5′ UUUCAAAGCUUUCUGAAUCUGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 235 (5′ AGAUUCAGAAAGCUUUGAAA 3′). 
     The present disclosure provides an isolated oligonucleotide comprising a sense strand and an anti-sense strand, wherein: the sense strand comprises a nucleotide sequence that is substantially identical to a region comprising 19-25 nucleotides between any one of the nucleotide positions selected from: a) 9 to 103; b) 110 to 504; c) 522 to 571; d) 612 to 653; e) 670 to 767; f) 836 to 964; g) 988 to 1128; h) 1145 to 1218; i) 1248 to 1309; j) 1351 to 1456; and k) 1501 to 1521, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1, and the anti-sense strand is substantially complementary to the sense strand such that the sense strand and the anti-sense strand together form a double stranded region. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% identical to a region comprising 19-25 nucleotides between any one of the nucleotide positions selected from: a) 9 to 103; b) 110 to 504; c) 522 to 571; d) 612 to 653; e) 670 to 767; f) 836 to 964; g) 988 to 1128; h) 1145 to 1218; i) 1248 to 1309; j) 1351 to 1456; and k) 1501 to 1521, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence that is identical to a region comprising 19-25 nucleotides between any one of the nucleotide positions selected from: a) 9 to 103; b) 110 to 504; c) 522 to 571; d) 612 to 653; e) 670 to 767; f) 836 to 964; g) 988 to 1128; h) 1145 to 1218; i) 1248 to 1309; j) 1351 to 1456; and k) 1501 to 1521, from the 5′ end of an ANGPTL-3 mRNA sequence according to SEQ ID NO: 1. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the anti-sense strand comprises a nucleotide sequence according to any one of: SEQ ID NOs: 2-62, 200, 268-411, and 523-633. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the sense strand comprises a nucleotide sequence according to any one of: SEQ ID NOs: 63-123, 235, 124-267, and 412-522. 
     In some embodiments of the isolated oligonucleotide of the present disclosure, the anti-sense strand comprises a nucleotide sequence according to any one of: SEQ ID NOs: 2-62, 200, 268-411, and 523-633; and the sense strand comprises a nucleotide sequence according to any one of: SEQ ID NOs: 63-123, 235, 124-267, and 412-522, wherein the anti-sense strand and the sense strand sequences have sufficient complementarity to allow formation of a double stranded region between the anti-sense and the sense strand. 
     In some embodiments, the isolated oligonucleotide of the present disclosure attenuates expression of the ANGPTL-3 mRNA in the liver by 20% to 50% (e.g., between 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 40% to 45% or 45% to 50%). 
     In some embodiments, the isolated oligonucleotide of the present disclosure attenuates expression of the ANGPTL-3 mRNA in the liver by 50 to 75% (e.g., between 50% to 55%, 55% to 60%, 60% to 65%, 65% to 70%, 70% to 75% or 75% to 80%). 
     In some embodiments, the isolated oligonucleotide of the present disclosure attenuates expression of the ANGPTL-3 mRNA in the liver by more than 75% (e.g., between 75% to 80%, 85% to 90%, 90% to 95%, 95% to 99%, or 99% to 100%). 
     In some embodiments of the isolated oligonucleotide of the present disclosure that attenuate expression of the ANGPTL-3 mRNA by 20% to 50%, 50% to 75%, or greater than 75% in the liver, the double stranded region comprises: i) an anti-sense of nucleotide sequence according to SEQ ID NO: 3 (5′ UAAAUUUUUACAUCGUCUAACA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 64 (5′ UUAGACGAUGUAAAAAUUUA 3′); ii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 4 (5′ UAUAAAAAGACUGAUCAAAUAU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 65 (5′ AUUUGAUCAGUCUUUUUAUA 3′); iii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 5 (5′ UGACAUAUUCUUUACCUCUUCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 66 (5′ AAGAGGUAAAGAAUAUGUCA 3′); iv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 9 (5′ UGAAAAACUUGAGAGUUGCUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 70 (5′ AGCAACUCUCAAGUUUUUCA 3′); v) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 10 (5′ UUAAUGUUUGUUGUCUUUCCAG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 71 (5′ GGAAAGACAACAAACAUUAA 3′); vi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 19 (5′ UCAUAGCAAAUCUUGAUUUUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 80 (5′ AAAAUCAAGAUUUGCUAUGA 3′); vii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 24 (5′ UGAUAGAUCAUAAAAAGACUGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 85 (5′ AGUCUUUUUAUGAUCUAUCA 3′); viii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 27 (5′ UUAGUUUAUAUGUAGUUCUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 88 (5′ AAGAACUACAUAUAAACUAA 3′); ix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 30 (5′ UUUAAGUUAGUUAGUUGCUCUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 91 (5′ GAGCAACUAACUAACUUAAA 3′); x) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 31 (5′ UAUUAAGUUAGUUAGUUGCUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 92 (5′ AGCAACUAACUAACUUAAUA 3′); xi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 34 (5′ UUUAGUUAGUUGCUCUUCUAAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 95 (5′ UAGAAGAGCAACUAACUAAA 3′); xii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 41 (5′ UUUGAAUUAAUGUCCAUGGACU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 102 (5′ UCCAUGGACAUUAAUUCAAA 3′); xiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 48 (5′ UUUUACAUCGUCUAACAUAGCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 109 (5′ CUAUGUUAGACGAUGUAAAA 3′); xiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 54 (5′ UUUAUAUGUAGUUCUUCUCAGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 115 (5′ UGAGAAGAACUACAUAUAAA 3′); xv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 55 (5′ UCAAGUGACAUAUUCUUUACCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 116 (5′ GUAAAGAAUAUGUCACUUGA 3′); xvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 56 (5′ UUUGAGUUGAGUUCAAGUGACA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 117 (5′ UCACUUGAACUCAACUCAAA 3′); xvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 60 (5′ UUUGUUGAAGUAGAAUUUUUUC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 121 (5′ AAAAAUUCUACUUCAACAAA 3′); xviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 61 (5′ UUUCACUUUUUGUUGAAGUAGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 122 (5′ UACUUCAACAAAAAGUGAAA 3′); xix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 62 (5′ UUUUAUUUGACUAUGCUGUUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 123 (5′ AACAGCAUAGUCAAAUAAAA 3′); xx) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 278 (5′ UUAGCAAAUCUUGAUUUUGGCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 134 (5′ CCAAAAUCAAGAUUUGCUAA 3′); xxi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 558 (5′ UAGAAUUUUUUCUUCUAGGAGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 447 (5′ UCCUAGAAGAAAAAAUUCUA 3′); xxii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 7 (5′ UUUUUAAGUGAAGUUACUUCUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 68 (5′ GAAGUAACUUCACUUAAAAA 3′); xxiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 2 (5′ UCAAUAAAAAGAAGGAGCUUAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 63 (5′ AAGCUCCUUCUUUUUAUUGA 3′); xxiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 11 (5′ UGUAUAACCUUCCAUUUUGAGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 72 (5′ UCAAAAUGGAAGGUUAUACA 3′); xxv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 15 (5′ UAUAAAAAGAAGGAGCUUAAUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 76 (5′ UUAAGCUCCUUCUUUUUAUA 3′); xxvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 17 (5′ UAAAUAACUAGAGGAACAAUAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 78 (5′ AUUGUUCCUCUAGUUAUUUA 3′); xxvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 18 (5′ UAAAUCUUGAUUUUGGCUCUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 79 (5′ AGAGCCAAAAUCAAGAUUUA 3′); xxviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 19 (5′ UCAUAGCAAAUCUUGAUUUUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 80 (5′ AAAAUCAAGAUUUGCUAUGA 3′); xxix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 20 (5′ UUUGAUUUUGGCUCUGGAGAUA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 81 (5′ UCUCCAGAGCCAAAAUCAAA 3′); xxx) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 21 (5′ UAUCGUCUAACAUAGCAAAUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 82 (5′ AUUUGCUAUGUUAGACGAUA 3′); xxxi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 22 (5′ UAUUUUUACAUCGUCUAACAUA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 83 (5′ UGUUAGACGAUGUAAAAAUA 3′); xxxii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 23 (5′ UAAAAUUUUUACAUCGUCUAAC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 84 (5′ UAGACGAUGUAAAAAUUUUA 3′); xxxiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 25 (5′ UUAAAAAGACUGAUCAAAUAUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 86 (5′ UAUUUGAUCAGUCUUUUUAA 3′); xxxiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 26 (5′ UAUAGAUCAUAAAAAGACUGAU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 87 (5′ CAGUCUUUUUAUGAUCUAUA 3′); xxxv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 28 (5′ UUUUAUAUGUAGUUCUUCUCAG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 89 (5′ GAGAAGAACUACAUAUAAAA 3′); xxxvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 29 (5′ UAUUUUUGACUUGUAGUUUAUA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 90 (5′ UAAACUACAAGUCAAAAAUA 3′); xxxvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 36 (5′ UAUGCUAUUAUCUUGUUUUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 97 (5′ AAAAACAAGAUAAUAGCAUA 3′); xxxviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 43 (5′ UUAAUUAGAUUGCUUCACUAUG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 104 (5′ UAGUGAAGCAAUCUAAUUAA 3′); xxxix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 45 (5′ UAUAUAAUGUUUGUUGUCUUUC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 106 (5′ AAGACAACAAACAUUAUAUA 3′); xL) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 46 (5′ UAAAGAAUAUUCAAUAUAAUGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 107 (5′ AUUAUAUUGAAUAUUCUUUA 3′); xLi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 6 (5′ UUUUAAGUGAAGUUACUUCUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 67 (5′ AGAAGUAACUUCACUUAAAA 3′); xLii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 12 (5′ UUUUAUAGAGUAUAACCUUCCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 73 (5′ GAAGGUUAUACUCUAUAAAA 3′); xLiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 57 (5′ UAAGUUAGUUAGUUGCUCUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 118 (5′ AAGAGCAACUAACUAACUUA 3′); xLiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 58 (5′ UGAAUUAAGUUAGUUAGUUGCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 119 (5′ CAACUAACUAACUUAAUUCA 3′); xLv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 280 (5′ UGUCUAACAUAGCAAAUCUUGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 136 (5′ AAGAUUUGCUAUGUUAGACA 3′); xLvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 296 (5′ UGACUGAUCAAAUAUGUUGAGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 152 (5′ UCAACAUAUUUGAUCAGUCA 3′); xLvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 316 (5′ UAAUUUUUUCUUCUAGGAGGCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 172 (5′ CCUCCUAGAAGAAAAAAUUA 3′); or xLviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 530 (5′ UUAAAAUUUUUACAUCGUCUAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 419 (5′ AGACGAUGUAAAAAUUUUAA 3′). 
     In some embodiments, the isolated oligonucleotide of the present disclosure attenuates expression of the ANGPTL-3 protein levels in serum by 20% to 50% (e.g., between 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 40% to 45% or 45% to 50%). 
     In some embodiments, the isolated oligonucleotide of the present disclosure attenuates expression of the ANGPTL-3 protein levels in serum by 50 to 75% (e.g., between 50% to 55%, 55% to 60%, 60% to 65%, 65% to 70%, 70% to 75% or 75% to 80%). 
     In some embodiments, the isolated oligonucleotide of the present disclosure attenuates expression of the ANGPTL-3 protein levels in serum by more than 75% (e.g., between 75% to 80%, 85% to 90%, 90% to 95%, 95% to 99%, or 99% to 100%). 
     In some embodiments of the isolated oligonucleotide of the present disclosure that attenuate expression of the ANGPTL-3 protein levels in serum by 20% to 50%, 50% to 75%, or greater than 75% in the liver, the double stranded region comprises: i) an anti-sense of nucleotide sequence according to SEQ ID NO: 3 (5′ UAAAUUUUUACAUCGUCUAACA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 64 (5′ UUAGACGAUGUAAAAAUUUA 3′); ii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 4 (5′ UAUAAAAAGACUGAUCAAAUAU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 65 (5′ AUUUGAUCAGUCUUUUUAUA 3′); iii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 5 (5′ UGACAUAUUCUUUACCUCUUCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 66 (5′ AAGAGGUAAAGAAUAUGUCA 3′); iv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 9 (5′ UGAAAAACUUGAGAGUUGCUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 70 (5′ AGCAACUCUCAAGUUUUUCA 3′); v) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 10 (5′ UUAAUGUUUGUUGUCUUUCCAG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 71 (5′ GGAAAGACAACAAACAUUAA 3′); 
     vi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 19 (5′ UCAUAGCAAAUCUUGAUUUUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 80 (5′ AAAAUCAAGAUUUGCUAUGA 3′); vii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 24 (5′ UGAUAGAUCAUAAAAAGACUGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 85 (5′ AGUCUUUUUAUGAUCUAUCA 3′); viii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 27 (5′ UUAGUUUAUAUGUAGUUCUUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 88 (5′ AAGAACUACAUAUAAACUAA 3′); ix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 30 (5′ UUUAAGUUAGUUAGUUGCUCUU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 91 (5′ GAGCAACUAACUAACUUAAA 3′); x) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 31 (5′ UAUUAAGUUAGUUAGUUGCUCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 92 (5′ AGCAACUAACUAACUUAAUA 3′); xi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 34 (5′ UUUAGUUAGUUGCUCUUCUAAA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 95 (5′ UAGAAGAGCAACUAACUAAA 3′); xii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 41 (5′ UUUGAAUUAAUGUCCAUGGACU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 102 (5′ UCCAUGGACAUUAAUUCAAA 3′); xiii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 48 (5′ UUUUACAUCGUCUAACAUAGCA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 109 (5′ CUAUGUUAGACGAUGUAAAA 3′); xiv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 54 (5′ UUUAUAUGUAGUUCUUCUCAGU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 115 (5′ UGAGAAGAACUACAUAUAAA 3′); xv) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 55 (5′ UCAAGUGACAUAUUCUUUACCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 116 (5′ GUAAAGAAUAUGUCACUUGA 3′); xvi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 56 (5′ UUUGAGUUGAGUUCAAGUGACA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 117 (5′ UCACUUGAACUCAACUCAAA 3′); xvii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 60 (5′ UUUGUUGAAGUAGAAUUUUUUC 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 121 (5′ AAAAAUUCUACUUCAACAAA 3′); xviii) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 61 (5′ UUUCACUUUUUGUUGAAGUAGA 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 122 (5′ UACUUCAACAAAAAGUGAAA 3′); xix) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 62 (5′ UUUUAUUUGACUAUGCUGUUGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 123 (5′ AACAGCAUAGUCAAAUAAAA 3′); xx) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 278 (5′ UUAGCAAAUCUUGAUUUUGGCU 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 134 (5′ CCAAAAUCAAGAUUUGCUAA 3′); or xxi) an anti-sense strand of nucleotide sequence according to SEQ ID NO: 558 (5′ UAGAAUUUUUUCUUCUAGGAGG 3′), and a sense strand of nucleotide sequence according to SEQ ID NO: 447 (5′ UCCUAGAAGAAAAAAUUCUA 3′). 
     In some embodiments, the isolated oligonucleotides of the present disclosure can comprises a linker, sometimes referred to as a loop. siRNAs comprising a linker or loop are sometimes referred to as short hairpin RNAs (shRNAs). In some embodiments, both the sense and the anti-sense regions of the siRNA are encoded by one single-stranded RNA. In these embodiments, and the anti-sense region and the sense region hybridize to form a duplex region. The sense and anti-sense regions are joined by a linker sequence, forming a “hairpin” or “stem-loop” structure. The siRNA can have complementary sense and anti-sense regions at opposing ends of a single stranded molecule, so that the molecule can form a duplex region with the complementary sequence portions, and the strands are linked at one end of the duplex region by a linker. The linker can be either a nucleotide or non-nucleotide linker or a combination thereof. The linker can interact with the first, and optionally, second strands through covalent bonds or non-covalent interactions. 
     Any suitable nucleotide linker sequence is envisaged as within the scope of the disclosure. An siRNA of this disclosure may include a nucleotide, non-nucleotide, or mixed nucleotide/non-nucleotide linker that joins the sense region of the nucleic acid to the anti-sense region of the nucleic acid. A nucleotide linker can be a linker of &gt;2 nucleotides in length, for example about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 nucleotides in length. 
     Examples of a non-nucleotide linker include an abasic nucleotide, polyether, polyamine, polyamide, peptide, carbohydrate, lipid, polyhydrocarbon, or other polymeric agents, for example polyethylene glycols such as those having from 2 to 100 ethylene glycol units. Some examples are described in Seela et al., Nucleic Acids Research, 1987, Vol. 15, pp. 3113-3129; Cload et al., J. Am. Chem. Soc, 1991, Vol. 113, pp. 6324-6326; Jaeschke et al., Tetrahedron Lett., 1993, Vol. 34, pp. 301; Arnold et al., WO 1989/002439; Usman et al., WO 1995/006731; Dudycz et al., WO 1995/011910, and Ferentz et al., J. Am. Chem. Soc, 1991, Vol. 113, pp. 4000-4002. 
     Examples of nucleotide linker sequences include, but are not limited to, AUG, CCC, UUCG, CCACC, AAGCAA, CCACACC and UUCAAGAGA. 
     In some embodiments, the isolated oligonucleotides of the present disclosure is an siRNA that can be a dsRNA of a length suitable as a Dicer substrate, which can be processed to produce a RISC active siRNA molecule. See, e.g., Rossi et al., US2005/0244858. 
     A Dicer substrate double stranded RNA (dsRNA) can be of a length sufficient that it is processed by Dicer to produce an active siRNA, and may further include one or more of the following properties: (i) the Dicer substrate dsRNA can be asymmetric, for example, having a 3′ overhang on the anti-sense strand, (ii) the Dicer substrate dsRNA can have a modified 3′ end on the sense strand to direct orientation of Dicer binding and processing of the dsRNA to an active siRNA, for example the incorporation of one or more DNA nucleotides, and (iii) the first and second strands of the Dicer substrate ds RNA can from 19-30 bp in length. 
     In some embodiments of the isolated oligonucleotides of the present disclosure, the sense strand or the anti-sense strand or both comprise one or more modified nucleotide(s). 
     In some embodiments, the isolated oligonucleotides of the present disclosure comprises at least one modified nucleotide(s). In some embodiments, the one or more modified nucleotide(s) increases the stability or potency or both of the isolated oligonucleotide. In some embodiments, the one or more modified nucleotide(s) increases the stability of the RNA duplex, and siRNA. 
     Modifications that increase RNA stability include, but are not limited to locked nucleic acids. As used herein, the term “locked nucleic acid” or “LNA” includes, but is not limited to, a modified RNA nucleotide in which the ribose moiety comprises a methylene bridge connecting the 2′ oxygen and the 4′ carbon. This methylene bridge locks the ribose in the 3′-endo confirmation, also known as the north confirmation, that is found in A-form RNA duplexes. The term inaccessible RNA can be used interchangeably with LNA. LNAs having a 2′-4′ cyclic linkage, as described in the International Patent Application WO 99/14226, WO 00/56746, WO 00/56748, and WO 00/66604, the contents of which are incorporated herein by reference. 
     In some embodiments, the one or more modified nucleotide comprises a phosphorothioate derivative or an acridinine substituted nucleotide. In some embodiments, the the isolated oligonucleotides of the present disclosure comprise a phosphate mimic at the 5′-terminus of antisense strand, including but not limited to vinyl-phosphonate or other phosphate analogues. 
     In some embodiments, the modified nucleotide comprises 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomet-hyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methyl-aminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N-isopenten-yladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, or 2, 6-diaminopurine. 
     Nucleic Acids and Vectors 
     The present disclosure also provides a vector encoding an isolated oligonucleotide disclosed herein. In some embodiments, the vector is any one of a plasmid, a cosmid or a viral vector. In some embodiments, the vector is an adenoviral vector. In some embodiments, the vector is a lentiviral vector. In some embodiments, the plasmid is an expression plasmid. 
     The disclosure provides nucleic acids comprising the sequences encoding the isolated oligonucleotides of the present disclosure (e.g., dsRNAs or siRNAs) targeting ANGPTL-3 described herein. 
     In some embodiments, the nucleic acids are ribonucleic acids (RNAs). In some embodiments, the nucleic acids are deoxyribonucleic acids (DNAs). The DNAs may be a vector or a plasmid, e.g., an expression vector. 
     A “vector” is any nucleic acid molecule for the cloning of and/or transfer of a nucleic acid into a cell. A vector may be a replicon to which another nucleotide sequence may be attached to allow for replication of the attached nucleotide sequence. A “replicon” can be any genetic element (e.g., plasmid, phage, cosmid, chromosome, viral genome) that functions as an autonomous unit of nucleic acid replication in vivo, i.e., capable of replication under its own control. The term “vector” includes both viral and nonviral (e.g., plasmid) nucleic acid molecules for introducing a nucleic acid into a cell in vitro, ex vivo, and/or in vivo. A large number of vectors known in the art may be used to manipulate nucleic acids, incorporate response elements and promoters into genes, etc. For example, the insertion of the nucleic acid fragments corresponding to response elements and promoters into a suitable vector can be accomplished by ligating the appropriate nucleic acid fragments into a chosen vector that has complementary cohesive termini. Alternatively, the ends of the nucleic acid molecules may be enzymatically modified or any site may be produced by ligating nucleotide sequences (linkers) to the nucleic acid termini Such vectors may be engineered to contain sequences encoding selectable markers that provide for the selection of cells that contain the vector and/or have incorporated the nucleic acid of the vector into the cellular genome. Such markers allow identification and/or selection of host cells that incorporate and express the proteins encoded by the marker. A “recombinant” vector refers to a viral or non-viral vector that comprises one or more heterologous nucleotide sequences (i.e., transgenes), e.g., two, three, four, five or more heterologous nucleotide sequences. 
     By the term “express” or “expression” of a polynucleotide coding sequence, it is meant that the sequence is transcribed, and optionally, translated. Typically, according to the present disclosure, expression of a coding sequence of the disclosure will result in production of the polypeptide of the disclosure. The entire expressed polypeptide or fragment can also function in intact cells without purification. 
     In some embodiments, the vector is an expression vector for manufacturing siRNAs of the disclosure. Exemplary expression vectors may comprise a sequence encoding the sense and/or anti-sense strand of the isolated oligonucleotide of the present disclosure, under the control of a suitable promoter for transcription. Interfering RNAs may be expressed from a variety of eukaryotic promoters known to those of ordinary skill in the art, including pol III promoters, such as the U6 or H1 promoters, or pol II promoters, such as the cytomegalovirus promoter. Those of skill in the art will recognize that these promoters can also be adapted to allow inducible expression of the interfering RNA. 
     The isolated oligonucleotide of the present disclosure (e.g., dsRNAs and siRNAs) can be expressed endogenously from plasmid or viral expression vectors, or from minimal expression cassettes, for example, PCR generated fragments comprising one or more promoters and an appropriate template or templates for transcribing the siRNA. Examples of commercially available plasmid-based expression vectors for shRNA include members of the pSilencer series (Ambion, Austin. Tex.) and pCpG-siRNA (InvivoGen. San Diego, Calif.). Examples of kits for production of PCR-generated shRNA expression cassettes include Silencer Express (Ambion, Austin, Tex.) and siXpress (Mirus, Madison. Wis.). 
     Viral vectors for the in vivo expression of the isolated oligonucleotides (e.g., siRNAs and dsRNAs) in eukaryotic cells are also contemplated as within the scope of the instant disclosure. Viral vectors may be derived from a variety of viruses including adenovirus, adeno-associated virus, lentivirus (e.g., HIV, FIV, and EIAV), and herpes virus. Examples of commercially available viral vectors for shRNA expression include pSilencer adeno (Ambion, Austin, Tex.) and pLenti6/BLOCK-iT™-DEST (Invitrogen, Carlsbad, Calif.). Selection of viral vectors, methods for expressing the siRNA from the vector and methods of delivering the viral vector, for example incorporated within a nanoparticle, are within the ordinary skill of one in the art. 
     It will be apparent to those skilled in the art that any suitable vector, optionally incorporated into a nanoparticle, can be used to deliver the isolated oligonucleotides of the present disclosure (e.g., dsRNAs or siRNAs) described herein to a cell or subject. The vector can be delivered to cells in vivo. In other embodiments, the vector can be delivered to cells ex vivo, and then cells containing the vector are delivered to the subject. The choice of delivery vector can be made based on a number of factors known in the art, including age and species of the target host, in vitro versus in vivo delivery, level and persistence of expression desired, intended purpose (e.g., for therapy or screening), the target cell or organ, route of delivery, size of the isolated polynucleotide, safety concerns, and the like. 
     Delivery Systems 
     The present disclosure also provides a delivery system comprising the isolated oligonucleotide disclosed herein or vector of the present disclosure encoding an isolated oligonucleotide disclosed herein. In some embodiments, the delivery system is any one of a liposome, a nanoparticle, a polymer based delivery system or a ligand-conjugate delivery system. In some embodiments, the ligand-conjugate delivery system comprises one or more of an antibody, a peptide, a sugar moiety or a combination thereof. 
     In some embodiments, the delivery system of the present disclosure comprise nanoparticles comprising the isolated oligonucleotides of the present disclosure (e.g., siRNA or dsRNAs) targeting a ANGTL-3 mRNA for degradation. 
     In some embodiments, the nanoparticle comprises a polymer-based nanoparticle, a lipid-polymer based nanoparticle, a metal based nanoparticle, a carbon nanotube based nanoparticle, a nanocrystal or a polymeric micelle. In some embodiments, the polymer-based nanoparticle comprises a multiblock copolymer, a diblock copolymer, a polymeric micelle or a hyperbranched macromolecule. In some embodiments, the polymer-based nanoparticle comprises a multiblock copolymer a diblock copolymer. In some embodiments, the polymer-based nanoparticle is pH responsive. In some embodiments, the polymer-based nanoparticle further comprises a buffering component. 
     In some embodiments, the delivery system comprises a liposome. Liposomes are spherical vesicles having at least one lipid bilayer, and in some embodiments, an aqueous core. In some embodiments, the lipid bilayer of the liposome may comprise phospholipids. An exemplary but non-limiting example of a phospholipid is phosphatidylcholine, but the lipid bilayer may comprise additional lipids, such as phosphatidylethanolamine. Liposomes may be multilamellar, i.e. consisting of several lamellar phase lipid bilayers, or unilamellar liposomes with a single lipid bilayer. Liposomes can be made in a particular size range that makes them viable targets for phagocytosis. Liposomes can range in size from 20 nm to 100 nm, 100 nm to 400 nm, 1 μM and larger, or 200 nm to 3 μM. Examples of lipidoids and lipid-based formulations are provided in U.S. Published Application 20090023673. In other embodiments, the one or more lipids are one or more cationic lipids. One skilled in the art will recognize which liposomes are appropriate for siRNA encapsulation. 
     In some embodiments, the liposome or the nanoparticle of the present disclosure comprises a micelle. A micelle is an aggregate of surfactant molecules. An exemplary micelle comprises an aggregate of amphiphilic macromolecules, polymers or copolymers in aqueous solution, wherein the hydrophilic head portions contact the surrounding solvent, while the hydrophobic tail regions are sequestered in the center of the micelle. 
     In some embodiments, the nanoparticle comprises a nanocrystal. Exemplary nanocrystals are crystalline particles with at least one dimension of less than 1000 nanometers, preferably of less than 100 nanometers. 
     In some embodiments, the nanoparticle comprises a polymer based nanoparticle. In some embodiments, the polymer comprises a multiblock copolymer, a diblock copolymer, a polymeric micelle or a hyperbranched macromolecule. In some embodiments, the particle comprises one or more cationic polymers. In some embodiments, the cationic polymer is chitosan, protamine, polylysine, polyhistidine, polyarginine or poly(ethylene)imine. In other embodiments, the one or more polymers contain the buffering component, degradable component, hydrophilic component, cleavable bond component or some combination thereof. 
     In some embodiments, the nanoparticles or some portion thereof are degradable. In other embodiments, the lipids and/or polymers of the nanoparticles are degradable. 
     In some embodiments, any of these delivery systems of the present disclosure can comprise a buffering component. In other embodiments, any of the of the present disclosure can comprise a buffering component and a degradable component. In still other embodiments, any of the of the present disclosure can comprise a buffering component and a hydrophilic component. In yet other embodiments, any of the of the present disclosure can comprise a buffering component and a cleavable bond component. In yet other embodiments, any of the of the present disclosure can comprise a buffering component, a degradable component and a hydrophilic component. In still other embodiments, any of the of the present disclosure can comprise a buffering component, a degradable component and a cleavable bond component. In further embodiments, any of the of the present disclosure can comprise a buffering component, a hydrophilic component and a cleavable bond component. In yet another embodiment, any of the of the present disclosure can comprise a buffering component, a degradable component, a hydrophilic component and a cleavable bond component. In some embodiments, the particle is composed of one or more polymers that contain any of the aforementioned combinations of components. 
     In some embodiments of the isolated oligonucleotides of the present disclosure, the delivery system comprises a ligand-conjugate delivery system. In some embodiments, the ligand-conjugate delivery system comprises one or more of an antibody, a peptide, a sugar moiety, lipid or a combination thereof 
     In further embodiments, the isolated oligonucleotide of the present disclosure targeting a ANGPTL-3 mRNA (e.g., siRNA or dsRNA) is conjugated to, complexed to, or encapsulated by the one or more lipids or polymers of the delivery system. In further embodiments, the isolated oligonucleotide of the present disclosure targeting a ANGPTL-3 mRNA (e.g., siRNA or dsRNA) can be encapsulated in the hollow core of a nanoparticle. Alternatively, or in addition, the isolated oligonucleotide of the present disclosure targeting a ANGPTL-3 mRNA (e.g., siRNA or dsRNA) can be incorporated into the lipid or polymer based shell of the delivery system, for example via intercalation. Alternatively, or in addition, the isolated oligonucleotide of the present disclosure targeting a ANGPTL-3 mRNA (e.g., siRNA or dsRNA) can be attached to the surface of the delivery system. In some embodiments, the isolated oligonucleotide of the present disclosure targeting a ANGPTL-3 mRNA (e.g., siRNA or dsRNA) is conjugated to one or more lipids or polymers of the delivery system, e.g. via covalent attachment. 
     In some embodiments, the ligand conjugate delivery system further comprises a targeting agent. In some embodiments, the targeting agent comprises a peptide ligand, a nucleotide ligand, a polysaccharide ligand, a fatty acid ligand, a lipid ligand, a small molecule ligand, an antibody, an antibody fragment, an antibody mimetic or an antibody mimetic fragment. 
     In some embodiments, the targeting agent comprises a binding partner for a cell surface protein that is upregulated or overexpressed or normally expressed in a target cell encoding ANGPTL-3 mRNA and expressing ANGPTL-3 protein. In some embodiments, the binding partner can be a transmembrane peptidoglycan expressed on the surface of many types of such cells. Targeting of cell surface protein by the delivery system of the present disclosure thus provides superior delivery and specificity of the compositions of the disclosure to target cells. In some embodiments, the target cell can be any one of an intestinal cell, an arterial cell, a cell of the cardiovascular system, a hepatocyte, a pancreatic cell or a combination thereof. 
     In some embodiments, the delivery system of the present disclosure comprises a polymer based delivery system. In some embodiments, polymer based delivery system comprises a blending polymer. In some embodiments, the blending polymer is a copolymer comprising a degradable component and hydrophilic component. In some embodiments, the degradable component of the blending polymer is a polyester, poly(ortho ester), poly(ethylene imine), poly(caprolactone), polyanhydride, poly(acrylic acid), polyglycolide or poly(urethane). In some embodiments, the degradable component of the blending polymer is poly(lactic acid) (PLA) or poly(lactic-co-glycolic acid) (PLGA). In some embodiments, the hydrophilic component of the blending polymer is a polyalkylene glycol or a polyalkylene oxide. In some embodiments, the polyalkylene glycol is polyethylene glycol (PEG). In other embodiments, the polyalkylene oxide is polyethylene oxide (PEO). 
     In some embodiments, the delivery system of the present disclosure is a polymer based nanoparticle. Polymer based nanoparticles comprise one or more polymers. In some embodiments, the one or more polymers comprise a polyester, poly(ortho ester), poly(ethylene imine), poly(caprolactone), polyanhydride, poly(acrylic acid), polyglycolide or poly(urethane). In still other embodiments, the one or more polymers comprise poly(lactic acid) (PLA) or poly(lactic-co-glycolic acid) (PLGA). In some embodiments, the one or more polymers comprise poly(lactic-co-glycolic acid) (PLGA). In some embodiments, the one or more polymers comprise poly(lactic acid) (PLA). In some embodiments, the one or more polymers comprise polyalkylene glycol or a polyalkylene oxide. In some embodiments, the polyalkylene glycol is polyethylene glycol (PEG) or the polyalkylene oxide is polyethylene oxide (PEO). 
     In some embodiments, the polymer-based nanoparticle comprises poly(lactic-co-glycolic acid) PLGA polymers. In some embodiments, the PLGA nanoparticle further comprises a targeting agent, as described herein. 
     In some embodiments, the delivery system of the present disclosure is a nanoparticle of average characteristic dimension of less than about 500 nm, 400 nm, 300 nm, 250 nm, 200 nm, 180 nm, 150 nm, 120 nm, 100 nm, 90 nm, 80 nm, 70 nm, 60 nm, 50 nm, 40 nm, 30 nm or 20 nm. In other embodiments, the nanoparticle has an average characteristic dimension of 10 nm, 20 nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 120 nm, 150 nm, 180 nm, 200 nm, 250 nm or 300 nm. In further embodiments, the nanoparticle has an average characteristic dimension of 10-500 nm, 10-400 nm, 10-300 nm, 10-250 nm, 10-200 nm, 10-150 nm, 10-100 nm, 10-75 nm, 10-50 nm, 50-500 nm, 50-400 nm, 50-300 nm, 50-200 nm, 50-150 nm, 50-100 nm, 50-75 nm, 100-500 nm, 100-400 nm, 100-300 nm, 100-250 nm, 100-200 nm, 100-150 nm, 150-500 nm, 150-400 nm, 150-300 nm, 150-250 nm, 150-200 nm, 200-500 nm, 200-400 nm, 200-300 nm, 200-250 nm, 200-500 nm, 200-400 nm or 200-300 nm. 
     Therapeutic Agents 
     In some embodiments, the delivery system of the present disclosure are administered with one or more additional therapeutic agents. In some embodiments, the additional therapeutic agents can be a steroid, an anti-inflammatory agent, an antibody, a fusion protein, a small molecule or combination thereof. 
     In some embodiments, the additional therapeutic agent is incorporated into a delivery system of the present disclosure comprising at least one isolated oligonucleotide targeting ANGPTL-3, disclosed herein. In some embodiments, the additional therapeutic agent is conjugated to, complexed to, or encapsulated by the one or more lipids or polymers of the delivery system. Additional therapeutic agents can be encapsulated in the hollow core of delivery system. Alternatively, or in addition, Additional therapeutic agents can be incorporated into the lipid or polymer based shell of the delivery system, for example via intercalation. Alternatively, or in addition, additional therapeutic agents can be attached to the surface of the delivery system. In some embodiments, the additional therapeutic agents are conjugated to one or more lipids or polymers of the delivery system, e.g. via covalent attachment. 
     In some embodiments, the additional therapeutic agent and the delivery system at least one isolated oligonucleotide targeting ANGPTL-3, disclosed herein, are formulated in the same composition. For example, the delivery system comprising isolated oligonucleotide of the present disclosure targeting ANGPTL-3 and the additional therapeutic agent can be formulated in the same pharmaceutical composition. 
     In some embodiments, the additional therapeutic agent and the delivery system comprises at least one isolated oligonucleotide targeting ANGPTL-3, disclosed herein are formulated as separate compositions, e.g., for separate administration to a subject. 
     Pharmaceutical Compositions 
     The present disclosure also provides a pharmaceutical composition comprising: an isolated oligonucleotide disclosed herein, a vector of the present disclosure encoding an isolated oligonucleotide disclosed herein, or a delivery system of the present disclosure, and a pharmaceutically acceptable carrier, diluent, or excipient. 
     The pharmaceutical compositions of the disclosure can optionally comprise therapeutic agents, pharmaceutical agents, carriers, adjuvants, dispersing agents, diluents, and the like. 
     In some embodiments, the pharmaceutical composition comprises a therapeutic agent, such as a chemotherapeutic agent. In some embodiments, the therapeutic agent is formulated in the delivery system comprising the one or more isolated oligonucleotides (e.g., dsRNA or siRNA) targeting ANGPTL-3 of the present disclosure. 
     In some embodiments, an additional therapeutic agent is not formulated in the delivery system comprising the one or more isolated oligonucleotides (e.g., dsRNA or siRNA) targeting ANGPTL-3 of the present disclosure, but both the delivery system and the therapeutic agent are formulated in the same pharmaceutical composition. In some embodiments, an additional therapeutic agent is not formulated in the delivery system comprising the one or more isolated oligonucleotides (e.g., dsRNA or siRNA) targeting ANGPTL-3 of the present disclosure, and the delivery system and the therapeutic agent are formulated in separate pharmaceutical compositions. 
     Pharmaceutical compositions can contain any of the reagents discussed above, and one or more of a pharmaceutically acceptable carrier, a diluent or an excipient. 
     A pharmaceutical composition is in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed agent) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active agent is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required. 
     As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. 
     “Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient. 
     A pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), intraperitoneal (into the body cavity) and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, intraperitoneal or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. These preparations can contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient. Aqueous and non-aqueous sterile suspensions can include suspending agents and thickening agents. The formulations can be presented in unit/dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or water-for-injection immediately prior to use. 
     The pharmaceutical compositions containing the nanoparticles described herein may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active agents into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen. 
     Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required nanoparticle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. 
     Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active age can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the agents in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or agents of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. 
     For administration by inhalation, the agents are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. 
     The pharmaceutical compositions of the present disclosure can be prepared with pharmaceutically acceptable carriers that will protect the one or more isolated oligonucleotides (e.g., dsRNAs or siRNAs) targeting ANGPTL-3 mRNA of the present disclosure against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art, and the materials can be obtained commercially. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811. 
     It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active agent calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active agent and the particular therapeutic effect to be achieved. 
     The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. 
     As used herein, “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. 
     Techniques for formulation and administration of the disclosed compositions of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, Pa. (1995). 
     All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure. 
     Methods of Making Isolated Oligonucleotides 
     Provided herein are methods of making the one or more oligonucleotides of (e.g., dsRNAs or siRNAs) targeting ANGPTL-3 of the present disclosure, and delivery systems comprising same. 
     The one or more oligonucleotides of (e.g., dsRNAs or siRNAs) targeting ANGPTL-3 of the present disclosure, may be generated exogenously by chemical synthesis, by in vitro transcription, or by cleavage of longer double-stranded RNA with Dicer or another appropriate nuclease with similar activity. Chemically synthesized siRNAs, produced from protected ribonucleoside phosphoramidites using a conventional DNA/RNA synthesizer, may be obtained from commercial suppliers. The siRNAs can be purified by extraction with a solvent or resin, precipitation, electrophoresis, chromatography, or a combination thereof, for example. Alternatively, siRNAs may be used with little if any purification to avoid losses due to sample processing. 
     In some embodiments, the one or more oligonucleotides of (e.g., dsRNAs or siRNAs) targeting ANGPTL-3 of the present disclosure can be produced using an expression vector into which a nucleic acid encoding the double stranded RNA has been cloned, for example under control of a suitable promoter. 
     In some embodiments, the one or more oligonucleotides of (e.g., dsRNAs or siRNAs) targeting ANGPTL-3 of the present disclosure can be incorporated in a delivery system of the present disclosure (e.g., a nanoparticle). 
     Delivery systems comprising dsRNAs or siRNAs of the disclosure can be prepared by any suitable means known in the art. For example, polymeric nanoparticles can be prepared using various methods including, but not limited to, solvent evaporation, spontaneous emulsification, solvent diffusion, desolation, dialysis, ionic gelation, nanoprecipitation, salting out, spray drying and supercritical fluid methods. The dispersion of preformed polymers and the polymerization of monomers are two additional strategies for preparation of polymeric nanoparticles. However, the choice of an appropriate method depends upon various factors, which will be known to the person of ordinary skill in the art. 
     Sterile injectable solutions comprising a delivery system of the disclosure can be prepared by incorporating the one or more isolated oligonucleotides (e.g. dsRNA and siRNA) targeting ANGPTL-3 disclosed herein, in the delivery systems (e.g. nanoparticle) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated herein, as required, followed by filtered sterilization. Alternatively, or in addition, sterilization can be achieved through other means such as radiation or gas. Generally, dispersions are prepared by incorporating the delivery particles into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze drying that yields a powder of delivery system comprising the one or more isolated oligonucleotides (e.g. dsRNA and siRNA) targeting ANGPTL-3 disclosed herein, plus any additional desired ingredient from a previously sterile filtered solution thereof. 
     Methods of Use 
     The present disclosure also provides a method of inhibiting or downregulating the expression or level of ANGPTL-3 in a subject in need thereof, wherein the method comprises administering to the subject an effective amount an isolated oligonucleotide disclosed herein, a vector of the of the present disclosure encoding an isolated oligonucleotide disclosed herein, a delivery system of the present disclosure, or a pharmaceutical composition of the present disclosure. 
     The present disclosure also provides a method of treating or preventing a disease or disorder associated with aberrant or increased expression or activity of ANGPTL-3 or a disease or disorder where ANGPTL-3 plays a role in a subject in need thereof, wherein the method comprises administering to the subject an effective amount an isolated oligonucleotide disclosed herein, a vector of the of the present disclosure encoding an isolated oligonucleotide disclosed herein, a delivery system of the present disclosure, or a pharmaceutical composition of the present disclosure. 
     The present disclosure also provides an isolated oligonucleotide disclosed herein, a vector of the of the present disclosure encoding an isolated oligonucleotide disclosed herein, a delivery system of the present disclosure, or a pharmaceutical composition of the present disclosure, for use in treatment or prevention of a disease or disorder associated with aberrant or increased expression or activity of ANGPTL-3 or a disease or disorder where ANGPTL-3 plays a role, in a subject in need thereof. 
     The present disclosure also provides use of an isolated oligonucleotide disclosed herein, a vector of the of the present disclosure encoding an isolated oligonucleotide disclosed herein, a delivery system of the present disclosure, or a pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treatment or prevention of a disease or disorder associated with aberrant or increased expression or activity of ANGPTL-3 or a disease or disorder where ANGPTL-3 plays a role in a subject in need thereof. 
     Provided herein are methods of inhibiting or downregulating ANGPTL-3 expression or activity in a cell, comprising contacting the cell with the one or more oligonucleotides (e.g., dsRNA or siRNA) targeting ANGPTL-3 as described herein. The one or more oligonucleotides (e.g., dsRNA or siRNA) targeting ANGPTL-3 as described herein can reduce or inhibit ANGPTL-3 activity through the RNAi pathway. The cell can be in vitro, in vivo or ex vivo. For example, the cell can be from a cell line, or in vivo in a subject in need thereof. 
     In some embodiments, the one or more oligonucleotides (e.g., dsRNA or siRNA) targeting ANGPTL-3 as described herein are capable of inducing RNAi-mediated degradation of an ANGPTL-3 mRNA in a cell of a subject. 
     As used herein, the terms “contacting,” “introducing” and “administering” are used interchangeably, and refer to a process by which dsRNA or siRNA of the present disclosure or a nucleic acid molecule encoding a dsRNA or siRNA of this disclosure is delivered to a cell, in order to inhibit or alter or modify expression of a target gene. The dsRNA may be administered in a number of ways, including, but not limited to, direct introduction into a cell (i.e., intracellularly) and/or extracellular introduction into a cavity, interstitial space, or into the circulation of the organism. 
     “Introducing” in the context of a cell or organism means presenting the nucleic acid molecule to the organism and/or cell in such a manner that the nucleic acid molecule gains access to the interior of a cell. Where more than one nucleic acid molecule is to be introduced these nucleic acid molecules can be assembled as part of a single polynucleotide or nucleic acid construct, or as separate polynucleotide or nucleic acid constructs, and can be located on the same or different nucleic acid constructs. Accordingly, these polynucleotides can be introduced into cells in a single transformation event or in separate transformation events. Thus, the term “transformation” as used herein refers to the introduction of a heterologous nucleic acid into a cell. Transformation of a cell may be stable or transient. 
     The term “inhibit” or “reduce” or grammatical variations thereof, as used herein, refer to a decrease or diminishment in the specified level or activity of at least about 5%, about 10%, about 15%, about 25%, about 35%, about 40%, about 50%, about 60%, about 75%, about 80%, about 90%, about 95% or more. In some embodiments, the inhibition or reduction results in little or essentially no detectible activity (at most, an insignificant amount, e.g., less than about 10% or even 5%). 
     In contrast, the term “increase” or grammatical variations thereof as used herein refers to an increase or elevation in the specified level or activity of at least about 5%, about 10%, about 15%, about 25%, about 35%, about 40%, about 50%, about 60%, about 75%, about 80%, about 90%, about 95% or more. Increases in activity can be described in terms of fold change. For example, activity can be increased 1.2×, 1.5×, 2×, 3×, 5×, 6×, 7×, 8×, 9×, 10× or more compared to a baseline level of activity. 
     As used herein, the term “IC50” or “IC 50  value” refers to the concentration of an agent where cell viability is reduced by half. The IC 50  is thus a measure of the effectiveness of an agent in inhibiting a biological process. In an exemplary model, cell lines are cultured using standard techniques, treated with any of the one or more oligonucleotides (e.g., dsRNA or siRNA) targeting ANGPTL-3 as described herein, and the IC 50  value of the oligonucleotides (e.g., dsRNA or siRNA) targeting ANGPTL-3 is calculated after 24, 48 and/or 72 hours to determine its effectiveness in downregulating or inhibiting the level of ANGPTL-3 mRNA or protein to 50%, as compared to the level of ANGPTL-3 mRNA or protein in an untreated cell or in the same cell before initiation of treatment with the isolated oligonucleotide. 
     Methods of monitoring of ANGPTL-3 mRNA and/or protein expression can be used to characterize gene silencing, and to determine the effectiveness of the compositions described herein. Expression of ANGPTL-3 may be evaluated by any known technique. Examples thereof include immunoprecipitations methods, utilizing ANGPTL-3 antibodies in assays such as ELISAs, Western Blot, or immunohistochemistry to visualize ANGPTL-3 protein expression in cells, or flow cytometry. Additional methods include various hybridization methods utilizing a nucleic acid that specifically hybridizes with a nucleic acid encoding ANGPTL-3 or a unique fragment thereof, or a transcription product (e.g., mRNA) or splicing product of said nucleic acid, Northern Blot methods, Southern blot methods, and various PCR-based methods such as RT-PCR, qPCR or digital droplet PCR. ANGPTL-3 mRNA expression may additionally be assessed using high throughput sequencing techniques. 
     Methods of assaying the effect of individual isolated oligonucleotides (e.g., dsRNA or siRNA) targeting ANGPTL-3 include transfecting representative cell lines with isolated oligonucleotides, and measuring viability. For example, cells from representative cell lines can be transfected using methods known in the art, such as the RNAiMAX Lipofectamine kit (Invitrogen, Carlsbad, Calif.), and cultured using any suitable technique known in the art. Optionally additional therapeutic agents as described herein can be added at variable concentrations to cell culture media following transfection. Following a suitable incubation period, such as 24-96 hours, cell viability can be measured using methods such as Cell Titer Glo 2.0 (Promega, CA) to determine cell viability, and/or ANGPTL-3 mRNA and protein levels can be assessed using the methods described herein. 
     In some embodiments of the methods of inhibiting or downregulating ANGPTL-3 expression or activity in a cell of the present disclosure, wherein the isolated oligonucleotide, the vector, the delivery system, or the pharmaceutical composition is administered parenterally. 
     In some embodiments of the methods of inhibiting or downregulating ANGPTL-3 expression or activity in a cell of the present disclosure, wherein the parenteral administration is intravenous, subcutaneous, intraperitoneal, or intramuscular. 
     In some embodiments of the methods of inhibiting or downregulating ANGPTL-3 expression or activity in a cell of the present disclosure, the subject is a human. In some embodiments of the methods of inhibiting or downregulating ANGPTL-3 expression or activity in a cell of the present disclosure, the subject has hypercholesterolemia, hypertriglyceridemia, coronary heart disease, peripheral arterial disease, stroke, type 2 diabetes or high blood pressure or a combination thereof. 
     In some embodiments of the methods of inhibiting or downregulating ANGPTL-3 expression or activity in a cell of the present disclosure, the method comprises administering the isolated oligonucleotide, the vector, the delivery system, or the pharmaceutical composition, in combination with at least a second therapeutic agent. 
     In some embodiments of the methods of inhibiting or downregulating ANGPTL-3 expression or activity in a cell of the present disclosure, the second therapeutic agent is an antibody, a small molecule drug, a peptide, a nucleotide molecule, or a combination thereof. 
     In some embodiments of the methods of inhibiting or downregulating ANGPTL-3 expression or activity in a cell of the present disclosure, the second therapeutic agent is an isolated oligonucleotide of the present disclosure. 
     The present disclosure also provides a method of inhibiting or downregulating the expression or level of ANGPTL-3 in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a first and at least a second oligonucleotides disclosed herein, wherein the first and at least second oligonucleotides comprise different sequences. 
     In some embodiments of the methods of inhibiting or downregulating ANGPTL-3 expression or activity in a cell of the present disclosure, wherein the first and at least second oligonucleotides are administered simultaneously. 
     In some embodiments of the methods of inhibiting or downregulating ANGPTL-3 expression or activity in a cell of the present disclosure, wherein the first and at least second oligonucleotides are administered sequentially. 
     In some embodiments of the methods of inhibiting or downregulating ANGPTL-3 expression or activity in a cell of the present disclosure, the subject is a human. In some embodiments of the methods of inhibiting or downregulating ANGPTL-3 expression or activity in a cell of the present disclosure, the subject has hypercholesterolemia, hypertriglyceridemia, coronary heart disease, peripheral arterial disease, stroke, type 2 diabetes or high blood pressure or a combination thereof. 
     In some embodiments of the method of treating or preventing a disease or disorder associated with aberrant or increased expression or activity of ANGPTL-3 or a disease or disorder where ANGPTL-3 plays a role of the present disclosure, the subject is a human. In some embodiments of the method of treating or preventing a disease or disorder associated with aberrant or increased expression or activity of ANGPTL-3 or a disease or disorder where ANGPTL-3 plays a role of the present disclosure, the disease or disorder is hypercholesterolemia, hypertriglyceridemia, coronary heart disease, peripheral arterial disease, stroke, type 2 diabetes or high blood pressure or a combination thereof. 
     In some embodiments of the use for treating or preventing a disease or disorder associated with aberrant or increased expression or activity of ANGPTL-3 or a disease or disorder where ANGPTL-3 plays a role of the present disclosure, the subject is a human. In some embodiments of the use for treating or preventing a disease or disorder associated with aberrant or increased expression or activity of ANGPTL-3 or a disease or disorder where ANGPTL-3 plays a role of the present disclosure, the disease or disorder is hypercholesterolemia, hypertriglyceridemia, coronary heart disease, peripheral arterial disease, stroke, type 2 diabetes or high blood pressure or a combination thereof. 
     In some embodiments of the use in the manufacture of a medicament for treatment or prevention of a disease or disorder associated with aberrant or increased expression or activity of ANGPTL-3 of the present disclosure, the subject is a human. In some embodiments of the use in the manufacture of a medicament for treatment or prevention of a disease or disorder associated with aberrant or increased expression or activity of ANGPTL-3 of the present disclosure of the present disclosure, the disease or disorder is hypercholesterolemia, hypertriglyceridemia, coronary heart disease, peripheral arterial disease, stroke, type 2 diabetes or high blood pressure or a combination thereof, treatment or prevention of a disease or disorder associated with aberrant or increased expression or activity of ANGPTL-3. 
     Routes of Administration 
     Nanoparticles comprising the one or more isolated oligonucleotides (e.g., dsRNA or siRNA) targeting ANGPTL-3 mRNA of the present disclosure can be administered to a subject by many of the well-known methods currently used for therapeutic treatment. For example, for treatment of mammalian diseases associated with expression or activity of ANGPTL-3, a compositions comprising the one or more isolated oligonucleotides (e.g., dsRNA or siRNA) targeting ANGPTL-3 mRNA of the present disclosure may be injected directly into cells, injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment. 
     The compositions comprising the one or more isolated oligonucleotides (e.g., dsRNA or siRNA) targeting ANGPTL-3 mRNA of the present disclosure can be administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In some embodiments, the parenteral administration comprises intramuscular, intraperitoneal, subcutaneous or intravenous administration. One skilled in the art will recognize the advantages of certain routes of administration. 
     Compositions of the disclosure may be administered parenterally. Systemic administration of compositions comprising nanoparticles of the disclosure can also be by intravenous, transmucosal, subcutaneous, intraperitoneal, intramuscular or transdermal means. For intravenous parenteral administration, compositions comprising nanoparticles may be administered by injection or by infusion. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. 
     Dosages 
     In therapeutic applications, the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing or treatment of the condition or symptom associated with expression or activity of ANGPTL-3. Dosages may vary depending on the age and size of the subject and the type and severity of the disease or disorder associated with ANGPTL-3 expression. 
     The term “effective amount” or “therapeutically effective amount”, as used interchangeably herein, refers to an amount of a pharmaceutical agent to treat, ameliorate, inhibit, downregulate or control the expression of ANGPTL-3 or symptoms associated with aberrant or abnormal expression of ANGPTL-3 in a subject, or to exhibit a detectable therapeutic or inhibitory effect in a subject. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject&#39;s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician. 
     For any of the one or more isolated oligonucleotides (e.g., dsRNA or siRNA) targeting ANGPTL-3 mRNA of the present disclosure, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. In some embodiments, a standard xenograft or patient derived xenograft mouse model can be used to determine the effectiveness of the one or more isolated oligonucleotides (e.g., dsRNA or siRNA) targeting ANGPTL-3 mRNA of the present disclosure. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., the maximum tolerated dose and no observable adverse effect dose. Pharmaceutical compositions that exhibit large therapeutic windows are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration. 
     Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation. 
     The dosage of nanoparticles comprising the one or more isolated oligonucleotides (e.g., dsRNA or siRNA) targeting ANGPTL-3 mRNA of the present disclosure, required depends on the choice of the route of administration; the nature of the formulation; the nature of the patient&#39;s illness; the subject&#39;s size, weight, surface area, age, and sex; other drugs being administered; and the judgment of the attending physician. Wide variations in the needed dosage are to be expected in view of the differing efficiencies of various routes of administration. For example, oral administration would be expected to require higher dosages than administration by intravenous injection (e.g., 2-, 3-, 4-, 6-, 8-, 10-; 20-, 50-, 100-, 150-, or more fold). Variations in these dosage levels can be adjusted using standard empirical routines for optimization as is well understood in the art. Administrations can be single or multiple. Encapsulation of the inhibitor in a suitable delivery vehicle (e.g., capsules or implantable devices) may increase the efficiency of delivery, particularly for oral delivery. 
     A therapeutically effective dose of the one or more isolated oligonucleotides (e.g., dsRNA or siRNA) targeting ANGPTL-3 mRNA of the present disclosure, can optionally be combined with approved amounts of therapeutic agents, and described herein. 
     Kits and Articles of Manufacture 
     The present disclosure also provides a kit comprising an isolated oligonucleotide disclosed herein, a vector of the present disclosure encoding an isolated oligonucleotide disclosed herein, a delivery system of the present disclosure, or a pharmaceutical composition of the present disclosure. 
     The kits are for use in the treatment of diseases related to abnormal or aberrant expression of ANGPTL-3, in a mammal. The kits are for use in downregulating or inhibiting expression of ANGPTL-3 partially or completely, in a mammal. In some embodiments, the mammal is a human, a mouse, a rat, a rabbit, a pig, a bovine, a canine, a feline, an ungulate, an ape, a monkey or an equine species. In some embodiments, the mammal is a human 
     Nanoparticles comprising the one or more isolated oligonucleotides (e.g., dsRNA or siRNA) targeting ANGPTL-3 mRNA of the present disclosure, can be lyophilized before being packaged in the kit, or can be provided in solution with a pharmaceutically acceptable carrier, diluent of excipient. 
     In some embodiments of the kits of the disclosure, the kit comprises a therapeutically effective amount of a composition comprising the delivery system of the present disclosure comprising one or more of the isolated oligonucleotides of the present disclosure targeting ANGPTL-3 (dsRNA or siRNA), and instructions for use of the same. In some embodiments, the kit further comprises at least one additional therapeutic agents, as described herein. 
     Articles of manufacture include, but are not limited to, instructions for use of the kit in treating diseases related to abnormal or aberrant expression of ANGPTL-3 or diseases related to expression of ANGPTL-3. 
     In some embodiments, the kits further comprise instructions for administering the isolated oligonucleotides, the vector, the delivery systems and the pharmaceutical compositions of the disclosure. 
     All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed invention. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Exemplary Sequences of the Present Application and Their Potency in vitro 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 % of gene 
                 % of gene 
               
               
                   
                 Position 
                   
                   
                 remaining 
                 remaining 
               
               
                   
                 of guide 
                 Guide strand 
                 Passenger strand 
                 at 0.02 nM 
                 at 0.1 nM 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 SEQ ID NOs 
                 strand 3′ 
                 sequence (5′-3′) 
                 sequence (5′-3′) 
                 Mean 
                 SEM 
                 Mean 
                 SEM 
               
               
                   
               
            
           
           
               
            
               
                 Set 1 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 (SEQ ID NO: 268: 
                 30 
                 UUUUCAAGCAACGUGGAACUGU 
                 AGUUCCACGUUGCUUGAAAA 
                 81.111533 
                 9.3184535 
                 32.645433 
                 1.2792951 
               
               
                 SEQ ID NO: 124) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 269: 
                 32 
                 UAAUUUCAAGCAACGUGGAACU 
                 UUCCACGUUGCUUGAAAUUA 
                 90.014133 
                 3.2787059 
                 53.587933 
                 3.6458452 
               
               
                 SEQ ID NO: 125) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 270: 
                 35 
                 UUUCAAUUUCAAGCAACGUGGA 
                 CACGUUGCUUGAAAUUGAAA 
                 80.0895 
                 1.7664802 
                 34.202767 
                 3.7888977 
               
               
                 SEQ ID NO: 126) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 271: 
                 36 
                 UUUUCAAUUUCAAGCAACGUGG 
                 ACGUUGCUUGAAAUUGAAAA 
                 80.907933 
                 3.3800739 
                 38.524933 
                 2.5584298 
               
               
                 SEQ ID NO: 127) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 272: 
                 38 
                 UAUUUUCAAUUUCAAGCAACGU 
                 GUUGCUUGAAAUUGAAAAUA 
                 86.937033 
                 3.9987882 
                 51.0402 
                 3.5539255 
               
               
                 SEQ ID NO: 128) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 273: 
                 39 
                 UGAUUUUCAAUUUCAAGCAACG 
                 UUGCUUGAAAUUGAAAAUCA 
                 71.221633 
                 2.6311449 
                 37.2264 
                 1.9406537 
               
               
                 SEQ ID NO: 129) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 14: 
                 
                 
                   73 
                 
                 
                   UAAAGAAGGAGCUUAAUUGUGA 
                 
                 
                   ACAAUUAAGCUCCUUCUUUA 
                 
                 
                   53.396667 
                 
                 
                   1.438037 
                 
                 
                   23.529267 
                 
                 
                   0.5921558 
                 
               
               
                 
                   SEQ ID NO: 75) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 47: 
                 
                 
                   75 
                 
                 
                   UAAAAAGAAGGAGCUUAAUUGU 
                 
                 
                   AAUUAAGCUCCUUCUUUUUA 
                 
                 
                   52.968 
                 
                 
                   1.0609924 
                 
                 
                   22.5403 
                 
                 
                   1.342357 
                 
               
               
                 
                   SEQ ID NO: 108) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 274: 
                 82 
                 UGAACAAUAAAAAGAAGGAGCU 
                 CUCCUUCUUUUUAUUGUUCA 
                 87.569467 
                 3.0060246 
                 53.4674 
                 2.9598334 
               
               
                 SEQ ID NO: 130) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 275: 
                 104 
                 UAUUCUGGAGGAAAUAACUAGA 
                 UAGUUAUUUCCUCCAGAAUA 
                 71.2664 
                 2.2272059 
                 35.677733 
                 1.013812 
               
               
                 SEQ ID NO: 131) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 276: 
                 131 
                 UGAAUCAAAUGAUGAAUUGUCU 
                 ACAAUUCAUCAUUUGAUUCA 
                 92.256833 
                 3.0100584 
                 58.2395 
                 5.878688 
               
               
                 SEQ ID NO: 132) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 277: 
                 158 
                 UAAUCUUGAUUUUGGCUCUGGA 
                 CAGAGCCAAAAUCAAGAUUA 
                 75.575767 
                 2.2352084 
                 35.933667 
                 0.5464555 
               
               
                 SEQ ID NO: 133) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 18: 
                 
                 
                   159 
                 
                 
                   UAAAUCUUGAUUUUGGCUCUGG 
                 
                 
                   AGAGCCAAAAUCAAGAUUUA 
                 
                 
                   43.241667 
                 
                 
                   2.7841908 
                 
                 
                   24.375967 
                 
                 
                   5.3728394 
                 
               
               
                 
                   SEQ ID NO: 79) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 278: 
                 163 
                 UUAGCAAAUCUUGAUUUUGGCU 
                 CCAAAAUCAAGAUUUGCUAA 
                 56.316767 
                 0.362523 
                 30.630633 
                 2.8476555 
               
               
                 SEQ ID NO: 134) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 279: 
                 164 
                 UAUAGCAAAUCUUGAUUUUGGC 
                 CAAAAUCAAGAUUUGCUAUA 
                 87.385267 
                 3.893047 
                 58.967033 
                 9.1935964 
               
               
                 SEQ ID NO: 135) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 19: 
                 
                 
                   165 
                 
                 
                   UCAUAGCAAAUCUUGAUUUUGG 
                 
                 
                   AAAAUCAAGAUUUGCUAUGA 
                 
                 
                   45.484367 
                 
                 
                   2.3409822 
                 
                 
                   26.341767 
                 
                 
                   4.0614731 
                 
               
               
                 
                   SEQ ID NO: 80) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 280: 
                 171 
                 UGUCUAACAUAGCAAAUCUUGA 
                 AAGAUUUGCUAUGUUAGACA 
                 64.104133 
                 3.0918068 
                 38.084767 
                 5.5515859 
               
               
                 SEQ ID NO: 136) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 48: 
                 
                 
                   179 
                 
                 
                   UUUUACAUCGUCUAACAUAGCA 
                 
                 
                   CUAUGUUAGACGAUGUAAAA 
                 
                 
                   50.159233 
                 
                 
                   4.767436 
                 
                 
                   27.929767 
                 
                 
                   4.1018037 
                 
               
               
                 
                   SEQ ID NO: 109) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 49: 
                 
                 
                   180 
                 
                 
                   UUUUUACAUCGUCUAACAUAGC 
                 
                 
                   UAUGUUAGACGAUGUAAAAA 
                 
                 
                   65.861167 
                 
                 
                   0.9343576 
                 
                 
                   30.1164 
                 
                 
                   1.81541 
                 
               
               
                 
                   SEQ ID NO: 110) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   SEQ ID NO: 3: 
                 
                 
                   184 
                 
                 
                   UAAAUUUUUACAUCGUCUAACA 
                 
                 
                   UUAGACGAUGUAAAAAUUUA 
                 
                 
                   53.736933 
                 
                 
                   0.9785624 
                 
                 
                   24.777 
                 
                 
                   1.1407125 
                 
               
               
                 
                   SEQ ID NO: 64) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 281: 
                 187 
                 UCUAAAAUUUUUACAUCGUCUA 
                 GACGAUGUAAAAAUUUUAGA 
                 100.01487 
                 2.9546284 
                 66.843167 
                 5.9206462 
               
               
                 SEQ ID NO: 137) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 282: 
                 206 
                 UAACUGAAGGAGGCCAUUGGCU 
                 CCAAUGGCCUCCUUCAGUUA 
                 97.9615 
                 1.139691 
                 54.3866 
                 3.9999251 
               
               
                 SEQ ID NO: 138) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 283: 
                 207 
                 UCAACUGAAGGAGGCCAUUGGC 
                 CAAUGGCCUCCUUCAGUUGA 
                 99.696733 
                 2.6662818 
                 73.7278 
                 2.6968611 
               
               
                 SEQ ID NO: 139) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 284: 
                 217 
                 UGACCAUGUCCCAACUGAAGGA 
                 CUUCAGUUGGGACAUGGUCA 
                 108.20177 
                 5.5042258 
                 92.5647 
                 1.7211104 
               
               
                 SEQ ID NO: 140) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 285: 
                 221 
                 UUUAAGACCAUGUCCCAACUGA 
                 AGUUGGGACAUGGUCUUAAA 
                 93.7201 
                 5.4120913 
                 75.122933 
                 6.4053112 
               
               
                 SEQ ID NO: 141) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 286: 
                 223 
                 UCUUUAAGACCAUGUCCCAACU 
                 UUGGGACAUGGUCUUAAAGA 
                 108.3241 
                 6.3785735 
                 102.46843 
                 6.1372659 
               
               
                 SEQ ID NO: 142) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 287: 
                 227 
                 UAAGUCUUUAAGACCAUGUCCC 
                 GACAUGGuCUUAAAGACUUA 
                 100.31113 
                 9.2975383 
                 85.192233 
                 3.1617187 
               
               
                 SEQ ID NO: 143) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 288: 
                 228 
                 UAAAGUCUUUAAGACCAUGUCC 
                 ACAUGGUCUUAAAGACUUUA 
                 102.038 
                 8.0583773 
                 88.811267 
                 4.0530443 
               
               
                 SEQ ID NO: 144) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 289: 
                 234 
                 UAUGGACAAAGUCUUUAAGACC 
                 UCUUAAAGACUUUGUCCAUA 
                 98.124233 
                 2.7328737 
                 80.361867 
                 6.4032413 
               
               
                 SEQ ID NO: 145) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 290: 
                 236 
                 UUUAUGGACAAAGUCUUUAAGA 
                 UUAAAGACUUUGUCCAUAAA 
                 97.103467 
                 0.6574211 
                 86.360567 
                 3.0221867 
               
               
                 SEQ ID NO: 146) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 291: 
                 262 
                 UAUAUGUCAUUAAUUUGGCCCU 
                 GGCCAAAUUAAUGACAUAUA 
                 84.003533 
                 0.6946951 
                 55.887133 
                 0.4712452 
               
               
                 SEQ ID NO: 147) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 292: 
                 263 
                 UAAUAUGUCAUUAAUUUGGCCC 
                 GCCAAAUUAAUGACAUAUUA 
                 63.596033 
                 5.3027637 
                 37.1758 
                 1.0957327 
               
               
                 SEQ ID NO: 148) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 293: 
                 264 
                 UAAAUAUGUCAUUAAUUUGGCC 
                 CCAAAUUAAUGACAUAUUUA 
                 87.641767 
                 2.0945498 
                 64.418533 
                 0.8667767 
               
               
                 SEQ ID NO: 149) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 294: 
                 265 
                 UGAAAUAUGUCAUUAAUUUGGC 
                 CAAAUUAAUGACAUAUUUCA 
                 85.362567 
                 2.3767474 
                 48.921933 
                 2.6741333 
               
               
                 SEQ ID NO: 150) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 295: 
                 275 
                 UUUGAGUUUUUGAAAUAUGUCA 
                 ACAUAUUUCAAAAACUCAAA 
                 66.1322 
                 1.6889226 
                 35.774067 
                 4.1253731 
               
               
                 SEQ ID NO: 151) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 296: 
                 290 
                 UGACUGAUCAAAUAUGUUGAGU 
                 UCAACAUAUUUGAUCAGUCA 
                 84.1016 
                 2.7374969 
                 51.850367 
                 4.7386264 
               
               
                 SEQ ID NO: 152) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 297: 
                 295 
                 UAAAAAGACUGAUCAAAUAUGU 
                 AUAUUUGAUCAGUCUUUUUA 
                 72.8498 
                 1.4487774 
                 43.286567 
                 2.4261051 
               
               
                 SEQ ID NO: 153) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 24; 
                 
                 
                   305 
                 
                 
                   UGAUAGAUCAUAAAAAGACUGA 
                 
                 
                   AGUCUUUUUAUGAUCUAUCA 
                 
                 
                   53.979033 
                 
                 
                   1.905561 
                 
                 
                   26.105867 
                 
                 
                   1.6276034 
                 
               
               
                 
                   SEQ ID NO: 85) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 298: 
                 328 
                 UCUUUGAUUUCACUGGUUUGCA 
                 CAAACCAGUGAAAUCAAAGA 
                 86.6326 
                 3.2865195 
                 44.776033 
                 4.4416589 
               
               
                 SEQ ID NO: 154) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 299: 
                 333 
                 UUUCUUCUUUGAUUUCACUGGU 
                 CAGUGAAAUCAAAGAAGAAA 
                 92.217433 
                 5.5940638 
                 59.213933 
                 5.8075015 
               
               
                 SEQ ID NO: 155) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 300: 
                 334 
                 UCUUCUUCUUUGAUUUCACUGG 
                 AGUGAAAUCAAAGAAGAAGA 
                 69.148367 
                 3.9724784 
                 31.315 
                 4.7646439 
               
               
                 SEQ ID NO: 156) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 301: 
                 336 
                 UUUCUUCUUCUUUGAUUUCACU 
                 UGAAAUCAAAGAAGAAGAAA 
                 87.131667 
                 5.427754 
                 58.7004 
                 6.4070105 
               
               
                 SEQ ID NO: 157) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 302: 
                 338 
                 UUUUUCUUCUUCUUUGAUUUCA 
                 AAAUCAAAGAAGAAGAAAAA 
                 92.6884 
                 12.279077 
                 34.9207 
                 19.948282 
               
               
                 SEQ ID NO: 158) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 303: 
                 343 
                 UGUUCCUUUUCUUCUUCUUUGA 
                 AAAGAAGAAGAAAAGGAACA 
                 98.193767 
                 5.2532341 
                 63.4527 
                 4.7471188 
               
               
                 SEQ ID NO: 159) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 304: 
                 347 
                 UCUCAGUUCCUUUUCUUCUUCU 
                 AAGAAGAAAAGGAACUGAGA 
                 85.2296 
                 3.6383759 
                 49.4382 
                 10.739607 
               
               
                 SEQ ID NO: 160) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 305: 
                 350 
                 UCUUCUCAGUUCCUUUUCUUCU 
                 AAGAAAAGGAACUGAGAAGA 
                 95.922733 
                 1.8398638 
                 48.673467 
                 2.4293042 
               
               
                 SEQ ID NO: 161) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 306: 
                 353 
                 UGUUCUUCUCAGUUCCUUUUCU 
                 AAAAGGAACUGAGAAGAACA 
                 94.5707 
                 6.3835906 
                 41.7594 
                 7.1734133 
               
               
                 SEQ ID NO: 162) 
                   
                   
                   
                   
                   
                   
                   
               
            
           
           
               
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 (SEQ ID NO: 53: 
                 
                   358 
                 
                 
                   UAUGUAGUUCUUCUCAGUUCCU 
                 
                 
                   GAACUGAGAAGAACUACAUA 
                 
                 
                   64.678 
                 
                 
                   1.6125137 
                 
                 
                   30.536533 
                 
                 
                   2.9373369 
                 
               
               
                 
                   SEQ ID NO: 114) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 307: 
                 359 
                 UUAUGUAGUUCUUCUCAGUUCC 
                 AACUGAGAAGAACUACAUAA 
                 79.186633 
                 10.01101 
                 47.830533 
                 10.387164 
               
               
                 SEQ ID NO: 163) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 54: 
                 
                 
                   362 
                 
                 
                   UUUAUAUGUAGUUCUUCUCAGU 
                 
                 
                   UGAGAAGAACUACAUAUAAA 
                 
                 
                   52.007667 
                 
                 
                   5.7221394 
                 
                 
                   23.992967 
                 
                 
                   3.3882784 
                 
               
               
                 
                   SEQ ID NO: 115) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 308: 
                 364 
                 UGUUUAUAUGUAGUUCUUCUCA 
                 AGAAGAACUACAUAUAAACA 
                 60.327833 
                 6.2015425 
                 44.081067 
                 12.308883 
               
               
                 SEQ ID NO: 164) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 27: 
                 
                 
                   366 
                 
                 
                   UUAGUUUAUAUGUAGUUCUUCU 
                 
                 
                   AAGAACUACAUAUAAACUAA 
                 
                 
                   63.427533 
                 
                 
                   2.85008 
                 
                 
                   28.985067 
                 
                 
                   4.8675553 
                 
               
               
                 
                   SEQ ID NO: 88) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 309: 
                 369 
                 UUUGUAGUUUAUAUGUAGUUCU 
                 AACUACAUAUAAACUACAAA 
                 62.857633 
                 7.055527 
                 36.931633 
                 7.0092183 
               
               
                 SEQ ID NO: 165) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 310: 
                 375 
                 UUUUGACUUGUAGUUUAUAUGU 
                 AUAUAAACUACAAGUCAAAA 
                 62.0823 
                 9.0672152 
                 50.7904 
                 27.221904 
               
               
                 SEQ ID NO: 166) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 311: 
                 389 
                 UUUUACCUCUUCAUUUUUGACU 
                 UCAAAAAUGAAGAGGUAAAA 
                 118.18367 
                 1.2517491 
                 50.8274 
                 3.8309279 
               
               
                 SEQ ID NO: 167) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 55: 
                 
                 
                   403 
                 
                 
                   UCAAGUGACAUAUUCUUUACCU 
                 
                 
                   GUAAAGAAUAUGUCACUUGA 
                 
                 
                   50.322667 
                 
                 
                   4.8073004 
                 
                 
                   23.886167 
                 
                 
                   3.1825861 
                 
               
               
                 
                   SEQ ID NO: 116) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 56: 
                 
                 
                   415 
                 
                 
                   UUUGAGUUGAGUUCAAGUGACA 
                 
                 
                   UCACUUGAACUCAACUCAAA 
                 
                 
                   69.345933 
                 
                 
                   15.4121 
                 
                 
                   31.234733 
                 
                 
                   1.8142841 
                 
               
               
                 
                   SEQ ID NO: 117) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 312: 
                 417 
                 UUUUUGAGUUGAGUUCAAGUGA 
                 ACUUGAACUCAACUCAAAAA 
                 80.624467 
                 7.0841712 
                 101.0632 
                 8.8073837 
               
               
                 SEQ ID NO: 168) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 313: 
                 425 
                 UCUUUCAAGUUUUGAGUUGAGU 
                 UCAACUCAAAACUUGAAAGA 
                 82.508533 
                 5.3567098 
                 55.001833 
                 3.5084995 
               
               
                 SEQ ID NO: 169) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 314: 
                 440 
                 UUUUUCUUCUAGGAGGCUUUCA 
                 AAAGCCUCCUAGAAGAAAAA 
                 87.816433 
                 2.6304888 
                 53.872633 
                 11.02833 
               
               
                 SEQ ID NO: 170) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 315: 
                 443 
                 UAUUUUUUCUUCUAGGAGGCUU 
                 GCCUCCUAGAAGAAAAAAUA 
                 57.2616 
                 4.95955 
                 35.023633 
                 3.3959716 
               
               
                 SEQ ID NO: 171) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 316: 
                 444 
                 UAAUUUUUUCUUCUAGGAGGCU 
                 CCUCCUAGAAGAAAAAAUUA 
                 55.3547 
                 7.9583484 
                 33.086767 
                 0.842275 
               
               
                 SEQ ID NO: 172) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 317: 
                 445 
                 UGAAUUUUUUCUUCUAGGAGGC 
                 CUCCUAGAAGAAAAAAUUCA 
                 65.170533 
                 9.0766225 
                 50.532433 
                 19.274533 
               
               
                 SEQ ID NO: 173) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 318: 
                 448 
                 UGUAGAAUUUUUUCUUCUAGGA 
                 CUAGAAGAAAAAAUUCUACA 
                 61.441067 
                 2.2395317 
                 40.896667 
                 5.4915157 
               
               
                 SEQ ID NO: 174) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 319: 
                 467 
                 UUAUUUCACUUUUUGUUGAAGU 
                 UUCAACAAAAAGUGAAAUAA 
                 53.604333 
                 5.6668526 
                 35.461133 
                 5.5902173 
               
               
                 SEQ ID NO: 175) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 320: 
                 470 
                 UAAAUAUUUCACUUUUUGUUGA 
                 AACAAAAAGUGAAAUAUUUA 
                 79.7731 
                 11.290485 
                 35.922333 
                 11.652346 
               
               
                 SEQ ID NO: 176) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 321: 
                 471 
                 UUAAAUAUUUCACUUUUUGUUG 
                 ACAAAAAGUGAAAUAUUUAA 
                 84.426767 
                 16.359293 
                 50.253133 
                 4.1183419 
               
               
                 SEQ ID NO: 177) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 322: 
                 472 
                 UCUAAAUAUUUCACUUUUUGUU 
                 CAAAAAGUGAAAUAUUUAGA 
                 65.2547 
                 3.9430278 
                 47.642033 
                 5.9982093 
               
               
                 SEQ ID NO: 178) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 323: 
                 481 
                 UGUUGCUCUUCUAAAUAUUUCA 
                 AAAUAUUUAGAAGAGCAACA 
                 95.753833 
                 6.3840088 
                 84.063433 
                 2.9916751 
               
               
                 SEQ ID NO: 179) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 57: 
                 
                 
                   491 
                 
                 
                   UAAGUUAGUUAGUUGCUCUUCU 
                 
                 
                   AAGAGCAACUAACUAACUUA 
                 
                 
                   33.247167 
                 
                 
                   4.7473982 
                 
                 
                   17.260267 
                 
                 
                   2.9985122 
                 
               
               
                 
                   SEQ ID NO: 118) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 30: 
                 
                 
                   493 
                 
                 
                   UUUAAGUUAGUUAGUUGCUCUU 
                 
                 
                   GAGCAACUAACUAACUUAAA 
                 
                 
                   60.394867 
                 
                 
                   8.550497 
                 
                 
                   30.0198 
                 
                 
                   2.6377085 
                 
               
               
                 
                   SEQ ID NO: 91) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 31: 
                 
                 
                   494 
                 
                 
                   UAUUAAGUUAGUUAGUUGCUCU 
                 
                 
                   AGCAACUAACUAACUUAAUA 
                 
                 
                   31.838033 
                 
                 
                   2.5026453 
                 
                 
                   16.757633 
                 
                 
                   1.0421251 
                 
               
               
                 
                   SEQ ID NO: 92) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 58: 
                 
                 
                   496 
                 
                 
                   UGAAUUAAGUUAGUUAGUUGCU 
                 
                 
                   CAACUAACUAACUUAAUUCA 
                 
                 
                   65.6962 
                 
                 
                   2.3828708 
                 
                 
                   25.028133 
                 
                 
                   2.342104 
                 
               
               
                 
                   SEQ ID NO: 119) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 324: 
                 500 
                 UUUUUGAAUUAAGUUAGUUAGU 
                 UAACUAACUUAAUUCAAAAA 
                 97.3836 
                 7.0199213 
                 46.2078 
                 8.8036166 
               
               
                 SEQ ID NO: 180) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 32: 
                 
                 
                   504 
                 
                 
                   UUUGAUUUUGAAUUAAGUUAGU 
                 
                 
                   UAACUUAAUUCAAAAUCAAA 
                 
                 
                   77.550233 
                 
                 
                   3.610039 
                 
                 
                   27.3279 
                 
                 
                   3.1461421 
                 
               
               
                 
                   SEQ ID NO: 93) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 6: 
                 
                 
                   543 
                 
                 
                   UUUUAAGUGAAGUUACUUCUGG 
                 
                 
                   AGAAGUAACUUCACUUAAAA 
                 
                 
                   45.7161 
                 
                 
                   3.488431 
                 
                 
                   17.9783 
                 
                 
                   1.5298929 
                 
               
               
                 
                   SEQ ID NO: 67) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 35: 
                 
                 
                   569 
                 
                 
                   UCUAUUAUCUUGUUUUUCUACA 
                 
                 
                   UAGAAAAACAAGAUAAUAGA 
                 
                 
                   65.361567 
                 
                 
                   2.3323769 
                 
                 
                   28.518867 
                 
                 
                   3.3703379 
                 
               
               
                 
                   SEQ ID NO: 96) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 325: 
                 577 
                 UCUUUGAUGCUAUUAUCUUGUU 
                 CAAGAUAAUAGCAUCAAAGA 
                 114.21473 
                 8.3015935 
                 72.113933 
                 5.4392455 
               
               
                 SEQ ID NO: 181) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 326: 
                 588 
                 UCUGGAGAAGGUCUUUGAUGCU 
                 CAUCAAAGACCUUCUCCAGA 
                 101.64243 
                 4.1554567 
                 57.086033 
                 1.3809388 
               
               
                 SEQ ID NO: 182) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 327: 
                 635 
                 UAUUUGACUAUGCUGUUGGUUU 
                 ACCAACAGCAUAGUCAAAUA 
                 94.039567 
                 4.742873 
                 48.877433 
                 1.4459471 
               
               
                 SEQ ID NO: 183) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 328: 
                 637 
                 UUUAUUUGACUAUGCUGUUGGU 
                 CAACAGCAUAGUCAAAUAAA 
                 111.3027 
                 5.3796013 
                 78.620533 
                 12.135312 
               
               
                 SEQ ID NO: 184) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 62: 
                 
                 
                   638 
                 
                 
                   UUUUAUUUGACUAUGCUGUUGG 
                 
                 
                   AACAGCAUAGUCAAAUAAAA 
                 
                 
                   62.323233 
                 
                 
                   5.6744147 
                 
                 
                   22.150367 
                 
                 
                   3.2152643 
                 
               
               
                 
                   SEQ ID NO: 123) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 329: 
                 640 
                 UCUUUUAUUUGACUAUGCUGUU 
                 CAGCAUAGUCAAAUAAAAGA 
                 90.1718 
                 1.3542803 
                 42.463733 
                 6.6050357 
               
               
                 SEQ ID NO: 185) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 330: 
                 643 
                 UUUUCUUUUAUUUGACUAUGCU 
                 CAUAGUCAAAUAAAAGAAAA 
                 76.853333 
                 3.3724043 
                 37.182733 
                 5.3393213 
               
               
                 SEQ ID NO: 186) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 331: 
                 644 
                 UAUUUCUUUUAUUUGACUAUGC 
                 AUAGUCAAAUAAAAGAAAUA 
                 137.05967 
                 9.7924733 
                 42.786633 
                 5.1706423 
               
               
                 SEQ ID NO: 187) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 332: 
                 648 
                 UUUCUAUUUCUUUUAUUUGACU 
                 UCAAAUAAAAGAAAUAGAAA 
                 140.03297 
                 9.4930861 
                 73.5336 
                 15.295446 
               
               
                 SEQ ID NO: 188) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 333: 
                 650 
                 UUUUUCUAUUUCUUUUAUUUGA 
                 AAAUAAAAGAAAUAGAAAAA 
                 137.60857 
                 18.117029 
                 69.188333 
                 13.17626 
               
               
                 SEQ ID NO: 189) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 334: 
                 692 
                 UGAAAUUUCUGUGGGUUCUUGA 
                 AAGAACCCACAGAAAUUUCA 
                 92.6653 
                 9.4770748 
                 41.4271 
                 5.4535003 
               
               
                 SEQ ID NO: 190) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 335: 
                 698 
                 UGAUAGAGAAAUUUCUGUGGGU 
                 CCACAGAAAUUUCUCUAUCA 
                 83.653067 
                 2.7519067 
                 45.535367 
                 6.702345 
               
               
                 SEQ ID NO: 191) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 37: 
                 
                 
                   700 
                 
                 
                   UAAGAUAGAGAAAUUUCUGUGG 
                 
                 
                   ACAGAAAUUUCUCUAUCUUA 
                 
                 
                   68.411667 
                 
                 
                   0.8878605 
                 
                 
                   28.9777 
                 
                 
                   1.7445077 
                 
               
               
                 
                   SEQ ID NO: 98) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 336: 
                 721 
                 UUUCUUGGUGCUCUUGGCUUGG 
                 AAGCCAAGAGCACCAAGAAA 
                 152.11207 
                 9.2513988 
                 111.08723 
                 51.913069 
               
               
                 SEQ ID NO: 192) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 337: 
                 724 
                 UUAGUUCUUGGUGCUCUUGGCU 
                 CCAAGAGCACCAAGAACUAA 
                 82.261967 
                 4.9682566 
                 42.907967 
                 5.7810435 
               
               
                 SEQ ID NO: 193) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 338: 
                 725 
                 UGUAGUUCUUGGUGCUCUUGGC 
                 CAAGAGCACCAAGAACUACA 
                 98.714333 
                 3.1006466 
                 54.5726 
                 10.375489 
               
               
                 SEQ ID NO: 194) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 339: 
                 735 
                 UAAGAAAGGGAGUAGUUCUUGG 
                 AAGAACUACUCCCUUUCUUA 
                 88.692933 
                 1.5607667 
                 43.971367 
                 6.8420604 
               
               
                 SEQ ID NO: 195) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 39: 
                 
                 
                   738 
                 
                 
                   UCUGAAGAAAGGGAGUAGUUCU 
                 
                 
                   AACUACUCCCUUUCUUCAGA 
                 
                 
                   68.641367 
                 
                 
                   5.654269 
                 
                 
                   28.614433 
                 
                 
                   4.9746183 
                 
               
               
                 
                   SEQ ID NO: 100) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 340: 
                 760 
                 UUUACAUUUCUUAUUUCAUUCA 
                 AAUGAAAUAAGAAAUGUAAA 
                 73.978633 
                 2.8610971 
                 45.126433 
                 3.4099763 
               
               
                 SEQ ID NO: 196) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 341: 
                 848 
                 UGAGUUGCUGGGUCUGAUGGCA 
                 CCAUCAGACCCAGCAACUCA 
                 99.093567 
                 2.4467283 
                 57.508933 
                 7.4624154 
               
               
                 SEQ ID NO: 197) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 342: 
                 853 
                 UCUUGAGAGUUGCUGGGUCUGA 
                 AGACCCAGCAACUCUCAAGA 
                 91.759 
                 3.4622054 
                 53.417167 
                 8.0953572 
               
               
                 SEQ ID NO: 198) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 343: 
                 855 
                 UAACUUGAGAGUUGCUGGGUCU 
                 ACCCAGCAACUCUCAAGUUA 
                 95.9127 
                 5.4609295 
                 59.1318 
                 10.959826 
               
               
                 SEQ ID NO: 199) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 40: 
                 
                 
                   857 
                 
                 
                   UAAAACUUGAGAGUUGCUGGGU 
                 
                 
                   CCAGCAACUCUCAAGUUUUA 
                 
                 
                   59.400233 
                 
                 
                   2.7747281 
                 
                 
                   24.045367 
                 
                 
                   4.229129 
                 
               
               
                 
                   SEQ ID NO: 101) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 344: 
                 858 
                 UAAAAACUUGAGAGUUGCUGGG 
                 CAGCAACUCUCAAGUUUUUA 
                 76.7912 
                 4.5216948 
                 45.182267 
                 8.819548 
               
               
                 SEQ ID NO: 634) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 9: 
                 
                 
                   859 
                 
                 
                   UGAAAAACUUGAGAGUUGCUGG 
                 
                 
                   AGCAACUCUCAAGUUUUUCA 
                 
                 
                   57.659033 
                 
                 
                   4.7496144 
                 
                 
                   23.821 
                 
                 
                   1.6344765 
                 
               
               
                 
                   SEQ ID NO: 70) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 345: 
                 861 
                 UAUGAAAAACUUGAGAGUUGCU 
                 CAACUCUCAAGUUUUUCAUA 
                 71.069233 
                 5.2775892 
                 58.444467 
                 20.132003 
               
               
                 SEQ ID NO: 201) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 346: 
                 867 
                 UGUAGACAUGAAAAACUUGAGA 
                 UCAAGUUUUUCAUGUCUACA 
                 81.9428 
                 5.4334955 
                 45.0543 
                 3.7082459 
               
               
                 SEQ ID NO: 202) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 347: 
                 900 
                 UUAAUGUCCAUGGACUACCUGA 
                 AGGUAGUCCAUGGACAUUAA 
                 67.274567 
                 4.2862834 
                 31.388467 
                 2.1035597 
               
               
                 SEQ ID NO: 203) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 348: 
                 902 
                 UAUUAAUGUCCAUGGACUACCU 
                 GUAGUCCAUGGACAUUAAUA 
                 108.7726 
                 7.9744193 
                 84.910067 
                 8.4569033 
               
               
                 SEQ ID NO: 204) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 349: 
                 903 
                 UAAUUAAUGUCCAUGGACUACC 
                 UAGUCCAUGGACAUUAAUUA 
                 77.622833 
                 2.5979571 
                 36.826867 
                 4.445192 
               
               
                 SEQ ID NO: 205) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 41: 
                 
                 
                   906 
                 
                 
                   UUUGAAUUAAUGUCCAUGGACU 
                 
                 
                   UCCAUGGACAUUAAUUCAAA 
                 
                 
                   71.157233 
                 
                 
                   3.7079924 
                 
                 
                   36.405733 
                 
                 
                   0.8768475 
                 
               
               
                 
                   SEQ ID NO: 102) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 350: 
                 909 
                 UAUGUUGAAUUAAUGUCCAUGG 
                 AUGGACAUUAAUUCAACAUA 
                 113.2428 
                 3.3691547 
                 81.756033 
                 19.427249 
               
               
                 SEQ ID NO: 206) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 351: 
                 915 
                 UUAUUCGAUGUUGAAUUAAUGU 
                 AUUAAUUCAACAUCGAAUAA 
                 132.1274 
                 21.339567 
                 58.182467 
                 10.000921 
               
               
                 SEQ ID NO: 207) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 352: 
                 929 
                 UUUUUGUGAUCCAUCUAUUCGA 
                 GAAUAGAUGGAUCACAAAAA 
                 185.28237 
                 28.947359 
                 93.806867 
                 15.706993 
               
               
                 SEQ ID NO: 208) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 353: 
                 930 
                 UGUUUUGUGAUCCAUCUAUUCG 
                 AAUAGAUGGAUCACAAAACA 
                 143.0759 
                 7.9791352 
                 61.372733 
                 15.539965 
               
               
                 SEQ ID NO: 209) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 354: 
                 935 
                 UUUGAAGUUUUGUGAUCCAUCU 
                 AUGGAUCACAAAACUUCAAA 
                 129.94767 
                 13.627957 
                 70.935 
                 8.4723531 
               
               
                 SEQ ID NO: 210) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 355: 
                 956 
                 UUUGUAGUUCUCCCACGUUUCA 
                 AAACGUGGGAGAACUACAAA 
                 148.64763 
                 13.5027 
                 110.03653 
                 11.744245 
               
               
                 SEQ ID NO: 211) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 356: 
                 960 
                 UAUAUUUGUAGUUCUCCCACGU 
                 GUGGGAGAACUACAAAUAUA 
                 132.17717 
                 12.151453 
                 104.19597 
                 29.315333 
               
               
                 SEQ ID NO: 212) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 357: 
                 961 
                 UCAUAUUUGUAGUUCUCCCACG 
                 UGGGAGAACUACAAAUAUGA 
                 103.725 
                 7.7607682 
                 47.876967 
                 6.2847505 
               
               
                 SEQ ID NO: 213) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 358: 
                 964 
                 UAACCAUAUUUGUAGUUCUCCC 
                 GAGAACUACAAAUAUGGUUA 
                 118.90777 
                 10.384789 
                 57.7426 
                 6.7707745 
               
               
                 SEQ ID NO: 214) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 42: 
                 
                 
                   965 
                 
                 
                   UAAACCAUAUUUGUAGUUCUCC 
                 
                 
                   AGAACUACAAAUAUGGUUUA 
                 
                 
                   82.127033 
                 
                 
                   9.8030209 
                 
                 
                   27.6747 
                 
                 
                   3.8724921 
                 
               
               
                 
                   SEQ ID NO: 103) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 359: 
                 1008 
                 UUAUCUUCUCUAGGCCCAACCA 
                 GUUGGGCCUAGAGAAGAUAA 
                 141.8275 
                 16.388851 
                 96.864367 
                 15.759358 
               
               
                 SEQ ID NO: 215) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 360: 
                 1009 
                 UAUAUCUUCUCUAGGCCCAACC 
                 UUGGGCCUAGAGAAGAUAUA 
                 125.25507 
                 7.9341453 
                 81.532133 
                 3.2216714 
               
               
                 SEQ ID NO: 216) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 361: 
                 1013 
                 UGAGUAUAUCUUCUCUAGGCCC 
                 GCCUAGAGAAGAUAUACUCA 
                 113.2969 
                 6.2405098 
                 69.3611 
                 18.425281 
               
               
                 SEQ ID NO: 217) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 362: 
                 1030 
                 UUAGAUUGCUUCACUAUGGAGU 
                 UCCAUAGUGAAGCAAUCUAA 
                 101.4948 
                 5.4443606 
                 47.836067 
                 8.3064239 
               
               
                 SEQ ID NO: 218) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 363: 
                 1032 
                 UAUUAGAUUGCUUCACUAUGGA 
                 CAUAGUGAAGCAAUCUAAUA 
                 94.281133 
                 9.8842229 
                 43.5399 
                 10.690291 
               
               
                 SEQ ID NO: 219) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 364: 
                 1033 
                 UAAUUAGAUUGCUUCACUAUGG 
                 AUAGUGAAGCAAUCUAAUUA 
                 80.2373 
                 8.3302341 
                 30.678633 
                 5.0638987 
               
               
                 SEQ ID NO: 220) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 365: 
                 1061 
                 UCAGUCUUCCAACUCAAUUCGU 
                 GAAUUGAGUUGGAAGACUGA 
                 109.6143 
                 7.1361751 
                 66.678467 
                 6.7831127 
               
               
                 SEQ ID NO: 221) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 366: 
                 1078 
                 UAAUGUUUGUUGUCUUUCCAGU 
                 UGGAAAGACAACAAACAUUA 
                 102.99897 
                 7.7998012 
                 55.368367 
                 3.3318317 
               
               
                 SEQ ID NO: 222) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 367: 
                 
                   1080 
                 
                 
                   UAUAAUGUUUGUUGUCUUUCCA 
                 
                 
                   GAAAGACAACAAACAUUAUA 
                 
                 
                   103.75123 
                 
                 
                   11.036301 
                 
                 
                   74.157033 
                 
                 
                   12.440365 
                 
               
               
                 SEQ ID NO: 223) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 44: 
                 
                 1081 
                 UUAUAAUGUUUGUUGUCUUUCC 
                 AAAGACAACAAACAUUAUAA 
                 72.085467 
                 6.0336195 
                 28.3018 
                 2.9335243 
               
               
                 
                   SEQ ID NO: 105) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 368: 
                 1084 
                 UCAAUAUAAUGUUUGUUGUCUU 
                 GACAACAAACAUUAUAUUGA 
                 109.78223 
                 8.1878628 
                 77.8338 
                 8.5819048 
               
               
                 SEQ ID NO: 224) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 369: 
                 1087 
                 UAUUCAAUAUAAUGUUUGUUGU 
                 AACAAACAUUAUAUUGAAUA 
                 126.2894 
                 7.5927047 
                 94.415 
                 12.560197 
               
               
                 SEQ ID NO: 225) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 370: 
                 1090 
                 UAAUAUUCAAUAUAAUGUUUGU 
                 AAACAUUAUAUUGAAUAUUA 
                 89.525567 
                 4.8574535 
                 43.538433 
                 11.119729 
               
               
                 SEQ ID NO: 226) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 371: 
                 1121 
                 UUAGUUGGUUUCGUGAUUUCCC 
                 GAAAUCACGAAACCAACUAA 
                 70.1635 
                 3.554717 
                 35.036967 
                 5.1468698 
               
               
                 SEQ ID NO: 227) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 372: 
                 1122 
                 UAUAGUUGGUUUCGUGAUUUCC 
                 AAAUCACGAAACCAACUAUA 
                 83.583633 
                 7.1836706 
                 57.0473 
                 7.5819033 
               
               
                 SEQ ID NO: 228) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 373: 
                 1129 
                 UGUAGCGUAUAGUUGGUUUCGU 
                 GAAACCAACUAUACGCUACA 
                 88.864933 
                 7.9989439 
                 46.698667 
                 1.0430542 
               
               
                 SEQ ID NO: 229) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 374: 
                 1166 
                 UAUUGCAUUGGGGACAUUGCCA 
                 GCAAUGUCCCCAAUGCAAUA 
                 88.390133 
                 10.063767 
                 46.541267 
                 3.1804305 
               
               
                 SEQ ID NO: 230) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 375: 
                 1167 
                 UGAUUGCAUUGGGGACAUUGCC 
                 CAAUGUCCCCAAUGCAAUCA 
                 115.077 
                 3.3146796 
                 111.374 
                 18.734875 
               
               
                 SEQ ID NO: 231) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 376: 
                 1176 
                 UGUUUUCCGGGAUUGCAUUGGG 
                 CAAUGCAAUCCCGGAAAACA 
                 94.2486 
                 11.377036 
                 81.139 
                 5.0015777 
               
               
                 SEQ ID NO: 232) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 377: 
                 1182 
                 UAUCUUUGUUUUCCGGGAUUGC 
                 AAUCCCGGAAAACAAAGAUA 
                 97.6698 
                 11.547892 
                 109.07143 
                 54.790767 
               
               
                 SEQ ID NO: 233) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 378: 
                 1188 
                 UCACCAAAUCUUUGUUUUCCGG 
                 GGAAAACAAAGAUUUGGUGA 
                 52.370733 
                 11.892447 
                 123.1813 
                 87.066701 
               
               
                 SEQ ID NO: 234) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 379: 
                 1195 
                 UUAGAAAACACCAAAUCUUUGU 
                 AAAGAUUUGGUGUUUUCUAA 
                 77.0324 
                 1.5308621 
                 43.206133 
                 9.2457205 
               
               
                 SEQ ID NO: 235) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 380: 
                 1204 
                 UGAUCCCAAGUAGAAAACACCA 
                 GUGUUUUCUACUUGGGAUCA 
                 103.65283 
                 8.106543 
                 129.6379 
                 40.457466 
               
               
                 SEQ ID NO: 236) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 381: 
                 1215 
                 UUUUUGCUUUGUGAUCCCAAGU 
                 UUGGGAUCACAAAGCAAAAA 
                 98.8224 
                 4.3587929 
                 76.0444 
                 11.570459 
               
               
                 SEQ ID NO: 237) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 382: 
                 1219 
                 UGUCCUUUUGCUUUGUGAUCCC 
                 GAUCACAAAGCAAAAGGACA 
                 104.02257 
                 6.1514778 
                 78.301967 
                 9.1899298 
               
               
                 SEQ ID NO: 238) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 383: 
                 1269 
                 UCUCAUCAUGCCACCACCAGCC 
                 CUGGUGGUGGCAUGAUGAGA 
                 103.70937 
                 8.1498855 
                 126.52803 
                 42.205361 
               
               
                 SEQ ID NO: 239) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 384: 
                 1273 
                 UCACACUCAUCAUGCCACCACC 
                 UGGUGGCAUGAUGAGUGUGA 
                 107.83373 
                 5.7365498 
                 99.9397 
                 1.3136097 
               
               
                 SEQ ID NO: 240) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 385: 
                 1279 
                 UUUUCUCCACACUCAUCAUGCC 
                 CAUGAUGAGUGUGGAGAAAA 
                 121.94393 
                 15.810038 
                 70.0712 
                 29.903818 
               
               
                 SEQ ID NO: 241) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 386: 
                 1280 
                 UUUUUCUCCACACUCAUCAUGC 
                 AUGAUGAGUGUGGAGAAAAA 
                 87.6833 
                 9.0146735 
                 43.7414 
                 18.931566 
               
               
                 SEQ ID NO: 242) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 387: 
                 1288 
                 UUUAGGUUGUUUUCUCCACACU 
                 UGUGGAGAAAACAACCUAAA 
                 22.05941 
                 90.047779 
                 65.621033 
                 23.955834 
               
               
                 SEQ ID NO: 243) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 388: 
                 1290 
                 UAUUUAGGUUGUUUUCUCCACA 
                 UGGAGAAAACAACCUAAAUA 
                 76.546567 
                 1.4885844 
                 51.554 
                 4.774882 
               
               
                 SEQ ID NO: 244) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 389: 
                 1300 
                 UUAUAUUUACCAUUUAGGUUGU 
                 AACCUAAAUGGUAAAUAUAA 
                 85.734367 
                 4.1702586 
                 62.483033 
                 4.8870038 
               
               
                 SEQ ID NO: 245) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 390: 
                 1301 
                 UUUAUAUUUACCAUUUAGGUUG 
                 ACCUAAAUGGUAAAUAUAAA 
                 68.444567 
                 7.471757 
                 41.968867 
                 5.2868984 
               
               
                 SEQ ID NO: 246) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 391: 
                 1302 
                 UGUUAUAUUUACCAUUUAGGUU 
                 CCUAAAUGGUAAAUAUAACA 
                 84.578233 
                 0.4915932 
                 40.932367 
                 18.304362 
               
               
                 SEQ ID NO: 247) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 392: 
                 1304 
                 UUUGUUAUAUUUACCAUUUAGG 
                 UAAAUGGUAAAUAUAACAAA 
                 75.169933 
                 0.3859007 
                 44.0614 
                 2.9868971 
               
               
                 SEQ ID NO: 248) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 393: 
                 1310 
                 UCUUGGUUUGUUAUAUUUACCA 
                 GUAAAUAUAACAAACCAAGA 
                 80.955133 
                 4.0044948 
                 52.750567 
                 5.9144115 
               
               
                 SEQ ID NO: 249) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 394: 
                 1372 
                 UAUAACCUUCCAUUUUGAGACU 
                 UCUCAAAAUGGAAGGUUAUA 
                 82.279633 
                 4.4737465 
                 56.732833 
                 5.0342632 
               
               
                 SEQ ID NO: 250) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 11: 
                 
                 
                   1374 
                 
                 
                   UGUAUAACCUUCCAUUUUGAGA 
                 
                 
                   UCAAAAUGGAAGGUUAUACA 
                 
                 
                   47.419233 
                 
                 
                   1.5257463 
                 
                 
                   20.3444 
                 
                 
                   1.6642044 
                 
               
               
                 
                   SEQ ID NO: 72) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 12: 
                 
                 
                   2382 
                 
                 
                   UUUUAUAGAGUAUAACCUUCCA 
                 
                 
                   GAAGGUUAUACUCUAUAAAA 
                 
                 
                   52.965733 
                 
                 
                   5.9697325 
                 
                 
                   25.163667 
                 
                 
                   4.6561875 
                 
               
               
                 
                   SEQ ID NO: 73) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 395: 
                 1383 
                 UUUUUAUAGAGUAUAACCUUCC 
                 AAGGUUAUACUCUAUAAAAA 
                 84.7974 
                 8.9870304 
                 40.742033 
                 10.249496 
               
               
                 SEQ ID NO: 251) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 396: 
                 1385 
                 UGAUUUUAUAGAGUAUAACCUU 
                 GGUUAUACUCUAUAAAAUCA 
                 90.5518 
                 5.754896 
                 47.735167 
                 14.146511 
               
               
                 SEQ ID NO: 252) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 13: 
                 
                 
                   2387 
                 
                 
                   UUUGAUUUUAUAGAGUAUAACC 
                 
                 
                   UUAUACUCUAUAAAAUCAAA 
                 
                 
                   49.542867 
                 
                 
                   5.4764675 
                 
                 
                   20.700367 
                 
                 
                   3.9959345 
                 
               
               
                 
                   SEQ ID NO: 74) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 397: 
                 1393 
                 UUUUUGGUUGAUUUUAUAGAGU 
                 UCUAUAAAAUCAACCAAAAA 
                 92.809833 
                 6.3035405 
                 50.460833 
                 5.3540639 
               
               
                 SEQ ID NO: 253) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 398: 
                 1395 
                 UCAUUUUGGUUGAUUUUAUAGA 
                 UAUAAAAUCAACCAAAAUGA 
                 64.130467 
                 2.0472791 
                 52.6753 
                 13.564506 
               
               
                 SEQ ID NO: 254) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 399: 
                 1404 
                 UAUGGAUCAACAUUUUGGUUGA 
                 AACCAAAAUGUUGAUCCAUA 
                 173.1365 
                 29.476142 
                 70.1206 
                 23.099461 
               
               
                 SEQ ID NO: 255) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 400: 
                 1417 
                 UCUGAAUCUGUUGGAUGGAUCA 
                 AUCCAUCCAACAGAUUCAGA 
                 87.26 
                 6.6062014 
                 71.0928 
                 11.558223 
               
               
                 SEQ ID NO: 256) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 401: 
                 1420 
                 UUUUCUGAAUCUGUUGGAUGGA 
                 CAUCCAACAGAUUCAGAAAA 
                 121.9751 
                 19.330767 
                 106.1185 
                 42.438487 
               
               
                 SEQ ID NO: 257) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 402: 
                 1421 
                 UCUUUCUGAAUCUGUUGGAUGG 
                 AUCCAACAGAUUCAGAAAGA 
                 96.614167 
                 7.881981 
                 63.7182 
                 9.1294267 
               
               
                 SEQ ID NO: 258) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 403: 
                 1424 
                 UAAGCUUUCUGAAUCUGUUGGA 
                 CAACAGAUUCAGAAAGCUUA 
                 62.765633 
                 5.2521074 
                 32.512133 
                 5.7431891 
               
               
                 SEQ ID NO: 259) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 200: 
                 
                 
                   2428 
                 
                 
                   UUUCAAAGCUUUCUGAAUCUGU 
                 
                 
                   AGAUUCAGAAAGCUUUGAAA 
                 
                 
                   50.476333 
                 
                 
                   1.9068653 
                 
                 
                   24.403067 
                 
                 
                   2.9538761 
                 
               
               
                 
                   SEQ ID NO: 235) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 404: 
                 1430 
                 UCAUUCAAAGCUUUCUGAAUCU 
                 AUUCAGAAAGCUUUGAAUGA 
                 77.107233 
                 4.6970322 
                 39.7077 
                 6.0068176 
               
               
                 SEQ ID NO: 260) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 405: 
                 1445 
                 UAAAUUUGCCUCAGUUCAUUCA 
                 AAUGAACUGAGGCAAAUUUA 
                 96.511567 
                 0.5075969 
                 64.195267 
                 5.3993091 
               
               
                 SEQ ID NO: 261) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 406: 
                 1449 
                 UUUUUAAAUUUGCCUCAGUUCA 
                 AACUGAGGCAAAUUUAAAAA 
                 92.577967 
                 2.5478732 
                 64.621 
                 7.5239279 
               
               
                 SEQ ID NO: 262) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 407: 
                 1450 
                 UCUUUUAAAUUUGCCUCAGUUC 
                 ACUGAGGCAAAUUUAAAAGA 
                 107.32393 
                 7.7834844 
                 66.103033 
                 2.0528362 
               
               
                 SEQ ID NO: 263) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 408: 
                 1454 
                 UUUGCCUUUUAAAUUUGCCUCA 
                 AGGCAAAUUUAAAAGGCAAA 
                 94.013167 
                 15.980062 
                 48.363467 
                 5.8449752 
               
               
                 SEQ ID NO: 264) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 409: 
                 1456 
                 UUAUUGCCUUUUAAAUUUGCCU 
                 GCAAAUUUAAAAGGCAAUAA 
                 84.605 
                 5.7726317 
                 56.793433 
                 19.518118 
               
               
                 SEQ ID NO: 265) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 410: 
                 1457 
                 UUUAUUGCCUUUUAAAUUUGCC 
                 CAAAUUUAAAAGGCAAUAAA 
                 74.781467 
                 2.3691634 
                 32.703633 
                 4.5081013 
               
               
                 SEQ ID NO: 266) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 411: 
                 1522 
                 UUUCUCUUAAGGAUUUAAUACC 
                 UAUUAAAUCCUUAAGAGAAA 
                 84.0109 
                 3.005092 
                 35.619533 
                 2.3364351 
               
               
                 SEQ ID NO: 267) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
            
           
           
               
            
               
                 Set 2 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 (SEQ ID NO: 523: 
                 33 
                 UCAAUUUCAAGCAACGUGGAAC 
                 UCCACGUUGCUUGAAAUUGA 
                 83.566667 
                 1.2128937 
                 59 
                 8 
               
               
                 SEQ ID NO: 412) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 524: 
                 37 
                 UUUUUCAAUUUCAAGCAACGUG 
                 CGUUGCUUGAAAUUGAAAAA 
                 68.7 
                 2.2501852 
                 29.6 
                 2.6102363 
               
               
                 SEQ ID NO: 413) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 525: 
                 62 
                 UUUAAUUGUGAACAUUUUUAUC 
                 UAAAAAUGUUCACAAUUAAA 
                 74.233333 
                 1.6796164 
                 27.833333 
                 2.338328 
               
               
                 SEQ ID NO: 414) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 526: 
                 63 
                 UCUUAAUUGUGAACAUUUUUAU 
                 AAAAAUGUUCACAAUUAAGA 
                 97.033333 
                 9.2405507 
                 53.966667 
                 3.0140412 
               
               
                 SEQ ID NO: 415) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 15: 
                 
                 
                   77 
                 
                 
                   UAUAAAAAGAAGGAGCUUAAUU 
                 
                 
                   UUAAGCUCCUUCUUUUUAUA 
                 
                 
                   47.166667 
                 
                 
                   3.7100464 
                 
                 
                   16.7 
                 
                 
                   2.007486 
                 
               
               
                 
                   SEQ ID NO: 76) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 16: 
                 
                 
                   78 
                 
                 
                   UAAUAAAAAGAAGGAGCUUAAU 
                 
                 
                   UAAGCUCCUUCUUUUUAUUA 
                 
                 
                   77.733333 
                 
                 
                   4.684134 
                 
                 
                   26.866667 
                 
                 
                   2.3835082 
                 
               
               
                 
                   SEQ ID NO: 77) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 2: 
                 
                 
                   79 
                 
                 
                   UCAAUAAAAAGAAGGAGCUUAA 
                 
                 
                   AAGCUCCUUCUUUUUAUUGA 
                 
                 
                   48.766667 
                 
                 
                   1.034945 
                 
                 
                   20.866667 
                 
                 
                   0.5044249 
                 
               
               
                 
                   SEQ ID NO: 63) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 17: 
                 
                 
                   94 
                 
                 
                   UAAAUAACUAGAGGAACAAUAA 
                 
                 
                   AUUGUUCCUCUAGUUAUUUA 
                 
                 
                   50.466667 
                 
                 
                   6.920822 
                 
                 
                   17.166667 
                 
                 
                   0.7446103 
                 
               
               
                 
                   SEQ ID NO: 78) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 527: 
                 98 
                 UGAGGAAAUAACUAGAGGAACA 
                 UUCCUCUAGUUAUUUCCUCA 
                 71.833333 
                 2.6491089 
                 37.1 
                 1.3453624 
               
               
                 SEQ ID NO: 416) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 20: 
                 
                 
                   154 
                 
                 
                   UUUGAUUUUGGCUCUGGAGAUA 
                 
                 
                   UCUCCAGAGCCAAAAUCAAA 
                 
                 
                   62.866667 
                 
                 
                   8.5159328 
                 
                 
                   21.933333 
                 
                 
                   0.664162 
                 
               
               
                 
                   SEQ ID NO: 81) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 528: 
                 155 
                 UCUUGAUUUUGGCUCUGGAGAU 
                 CUCCAGAGCCAAAAUCAAGA 
                 80.966667 
                 15.908523 
                 37.2 
                 7.4002252 
               
               
                 SEQ ID NO: 417) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 50: 
                 
                 
                   169 
                 
                 
                   UCUAACAUAGCAAAUCUUGAUU 
                 
                 
                   UCAAGAUUUGCUAUGUUAGA 
                 
                 
                   63.7 
                 
                 
                   11.475191 
                 
                 
                   22.233333 
                 
                 
                   2.2578259 
                 
               
               
                 
                   SEQ ID NO: 111) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 21: 
                 
                 
                   174 
                 
                 
                   UAUCGUCUAACAUAGCAAAUCU 
                 
                 
                   AUUUGCUAUGUUAGACGAUA 
                 
                 
                   54.666667 
                 
                 
                   8.5623854 
                 
                 
                   22.166667 
                 
                 
                   1.3928409 
                 
               
               
                 
                   SEQ ID NO: 82) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 529: 
                 181 
                 UUUUUUACAUCGUCUAACAUAG 
                 AUGUUAGACGAUGUAAAAAA 
                 67.566667 
                 8.2795598 
                 30.266667 
                 2.2578259 
               
               
                 SEQ ID NO: 418) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 22: 
                 
                 
                   182 
                 
                 
                   UAUUUUUACAUCGUCUAACAUA 
                 
                 
                   UGUUAGACGAUGUAAAAAUA 
                 
                 
                   46.333333 
                 
                 
                   3.5783298 
                 
                 
                   13.466667 
                 
                 
                   0.5607535 
                 
               
               
                 
                   SEQ ID NO: 83) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 23: 
                 
                 
                   185 
                 
                 
                   UAAAAUUUUUACAUCGUCUAAC 
                 
                 
                   UAGACGAUGUAAAAAUUUUA 
                 
                 
                   40.5 
                 
                 
                   3.356089 
                 
                 
                   13.733333 
                 
                 
                   1.4518188 
                 
               
               
                 
                   SEQ ID NO: 84) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 530: 
                 186 
                 UUAAAAUUUUUACAUCGUCUAA 
                 AGACGAUGUAAAAAUUUUAA 
                 46.1 
                 3.7233497 
                 27.3 
                 0.305505 
               
               
                 SEQ ID NO: 419) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 531: 
                 225 
                 UGUCUUUAAGACCAUGUCCCAA 
                 GGGACAUGGUCUUAAAGACA 
                 74.133333 
                 6.2135157 
                 70.433333 
                 8.0470146 
               
               
                 SEQ ID NO: 420) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 532: 
                 226 
                 UAGUCUUUAAGACCAUGUCCCA 
                 GGACAUGGUCUUAAAGACUA 
                 128.2 
                 6.7039789 
                 88.866667 
                 2.3103631 
               
               
                 SEQ ID NO: 421) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 533: 
                 229 
                 UCAAAGUCUUUAAGACCAUGUC 
                 CAUGGUCUUAAAGACUUUGA 
                 156.33333 
                 15.975015 
                 109.56667 
                 15.163809 
               
               
                 SEQ ID NO: 422) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 534: 
                 239 
                 UGUCUUAUGGACAAAGUCUUUA 
                 AAGACUUUGUCCAUAAGACA 
                 134.16667 
                 8.6971898 
                 109.2 
                 10.700156 
               
               
                 SEQ ID NO: 423) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 51: 
                 
                 
                   267 
                 
                 
                   UUUGAAAUAUGUCAUUAAUUUG 
                 
                 
                   AAUUAAUGACAUAUUUCAAA 
                 
                 
                   63.7 
                 
                 
                   3.5341194 
                 
                 
                   23.233333 
                 
                 
                   3.2844753 
                 
               
               
                 
                   SEQ ID NO: 112) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 535: 
                 270 
                 UUUUUUGAAAUAUGUCAUUAAU 
                 UAAUGACAUAUUUCAAAAAA 
                 130.53333 
                 17.288757 
                 64.633333 
                 7.4601906 
               
               
                 SEQ ID NO: 424) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 536: 
                 271 
                 UGUUUUUGAAAUAUGUCAUUAA 
                 AAUGACAUAUUUCAAAAACA 
                 91.733333 
                 5.621783 
                 36.633333 
                 2.9672284 
               
               
                 SEQ ID NO: 425) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 537: 
                 282 
                 UAAAUAUGUUGAGUUUUUGAAA 
                 UCAAAAACUCAACAUAUUUA 
                 77 
                 0.305505 
                 37.2 
                 2.9715316 
               
               
                 SEQ ID NO: 426) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 52: 
                 
                 
                   283 
                 
                 
                   UCAAAUAUGUUGAGUUUUUGAA 
                 
                 
                   CAAAAACUCAACAUAUUUGA 
                 
                 
                   71.3 
                 
                 
                   3.8850139 
                 
                 
                   26.633333 
                 
                 
                   2.6834886 
                 
               
               
                 
                   SEQ ID NO: 113) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 538: 
                 285 
                 UAUCAAAUAUGUUGAGUUUUUG 
                 AAAACUCAACAUAUUUGAUA 
                 88.466667 
                 3.8324637 
                 35.4 
                 0.3511885 
               
               
                 SEQ ID NO: 427) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 25: 
                 
                 
                   296 
                 
                 
                   UUAAAAAGACUGAUCAAAUAUG 
                 
                 
                   UAUUUGAUCAGUCUUUUUAA 
                 
                 
                   56.933333 
                 
                 
                   6.7296194 
                 
                 
                   22.033333 
                 
                 
                   2.1137118 
                 
               
               
                 
                   SEQ ID NO: 86) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 4: 
                 
                 
                   297 
                 
                 
                   UAUAAAAAGACUGAUCAAAUAU 
                 
                 
                   AUUUGAUCAGUCUUUUUAUA 
                 
                 
                   62.366667 
                 
                 
                   1.449521 
                 
                 
                   25.633333 
                 
                 
                   3.6956431 
                 
               
               
                 
                   SEQ ID NO: 65) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 539: 
                 301 
                 UGAUCAUAAAAAGACUGAUCAA 
                 GAUCAGUCUUUUUAUGAUCA 
                 96.533333 
                 8.0718303 
                 55.4 
                 2.007486 
               
               
                 SEQ ID NO: 428) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 26: 
                 
                 
                   304 
                 
                 
                   UAUAGAUCAUAAAAAGACUGAU 
                 
                 
                   CAGUCUUUUUAUGAUCUAUA 
                 
                 
                   52.333333 
                 
                 
                   2.5392475 
                 
                 
                   22.666667 
                 
                 
                   2.2519128 
                 
               
               
                 
                   SEQ ID NO: 87) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 540: 
                 327 
                 UUUUGAUUUCACUGGUUUGCAG 
                 GCAAACCAGUGAAAUCAAAA 
                 101.9 
                 9.4959641 
                 66.3 
                 8.3 
               
               
                 SEQ ID NO: 429) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 541: 
                 330 
                 UUUCUUUGAUUUCACUGGUUUG 
                 AACCAGUGAAAUCAAAGAAA 
                 87.1 
                 3.5104606 
                 40 
                 2.2538855 
               
               
                 SEQ ID NO: 430) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 542: 
                 337 
                 UUUUCUUCUUCUUUGAUUUCAC 
                 GAAAUCAAAGAAGAAGAAAA 
                 119.03333 
                 9.7160234 
                 37.266667 
                 2.9812376 
               
               
                 SEQ ID NO: 431) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 543: 
                 339 
                 UCUUUUCUUCUUCUUUGAUUUC 
                 AAUCAAAGAAGAAGAAAAGA 
                 79.2 
                 3.9374272 
                 34.333333 
                 2.490203 
               
               
                 SEQ ID NO: 432) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 544: 
                 356 
                 UGUAGUUCUUCUCAGUUCCUUU 
                 AGGAACUGAGAAGAACUACA 
                 79.533333 
                 3.0112751 
                 31.966667 
                 2.5692628 
               
               
                 SEQ ID NO: 433) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 545: 
                 360 
                 UAUAUGUAGUUCUUCUCAGUUC 
                 ACUGAGAAGAACUACAUAUA 
                 72.733333 
                 7.0390182 
                 29.2 
                 0.1527525 
               
               
                 SEQ ID NO: 434) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 28: 
                 
                 
                   363 
                 
                 
                   UUUUAUAUGUAGUUCUUCUCAG 
                 
                 
                   GAGAAGAACUACAUAUAAAA 
                 
                 
                   51.733333 
                 
                 
                   2.8904056 
                 
                 
                   18.6 
                 
                 
                   0.7211103 
                 
               
               
                 
                   SSEQ ID NO: 89) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 546: 
                 370 
                 UCUUGUAGUUUAUAUGUAGUUC 
                 ACUACAUAUAAACUACAAGA 
                 87.6 
                 7.7105988 
                 52.333333 
                 2.3680747 
               
               
                 SEQ ID NO: 435) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 547: 
                 372 
                 UGACUUGUAGUUUAUAUGUAGU 
                 UACAUAUAAACUACAAGUCA 
                 84.433333 
                 8.2870046 
                 44.633333 
                 5.2333333 
               
               
                 SEQ ID NO: 436) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 548: 
                 376 
                 UUUUUGACUUGUAGUUUAUAUG 
                 UAUAAACUACAAGUCAAAAA 
                 77.1 
                 4.0037482 
                 59.466667 
                 2.3974524 
               
               
                 SEQ ID NO: 437) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 29: 
                 
                 
                   378 
                 
                 
                   UAUUUUUGACUUGUAGUUUAUA 
                 
                 
                   UAAACUACAAGUCAAAAAUA 
                 
                 
                   48.4 
                 
                 
                   2.136196 
                 
                 
                   21.833333 
                 
                 
                   1.2018504 
                 
               
               
                 
                   SEQ ID NO:  
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                 
                   SEQ ID NO: 90) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 549: 
                 379 
                 UCAUUUUUGACUUGUAGUUUAU 
                 AAACUACAAGUCAAAAAUGA 
                 95.466667 
                 2.3694819 
                 43.8 
                 4.7843495 
               
               
                 SEQ ID NO: 438) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 550: 
                 381 
                 UUUCAUUUUUGACUUGUAGUUU 
                 ACUACAAGUCAAAAAUGAAA 
                 82.6 
                 4.6479386 
                 32.8 
                 4.8839874 
               
               
                 SEQ ID NO: 439) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 551: 
                 393 
                 UAUUCUUUACCUCUUCAUUUUU 
                 AAAUGAAGAGGUAAAGAAUA 
                 97.4 
                 5.3500779 
                 50.866667 
                 5.1414438 
               
               
                 SEQ ID NO: 440) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 552: 
                 396 
                 UCAUAUUCUUUACCUCUUCAUU 
                 UGAAGAGGUAAAGAAUAUGA 
                 89.4 
                 10.695949 
                 62.166667 
                 6.1690986 
               
               
                 SEQ ID NO: 441) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 5: 
                 
                 
                   398 
                 
                 
                   UGACAUAUUCUUUACCUCUUCA 
                 
                 
                   AAGAGGUAAAGAAUAUGUCA 
                 
                 
                   57.566667 
                 
                 
                   4.9092882 
                 
                 
                   20.7 
                 
                 
                   1.8520259 
                 
               
               
                 
                   SEQ ID NO: 66) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 553: 
                 418 
                 UGUUUUGAGUUGAGUUCAAGUG 
                 CUUGAACUCAACUCAAAACA 
                 87 
                 2.4131584 
                 52 
                 5.4009258 
               
               
                 SEQ ID NO: 442) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 554: 
                 438 
                 UUUCUUCUAGGAGGCUUUCAAG 
                 UGAAAGCCUCCUAGAAGAAA 
                 96.733333 
                 4.7054342 
                 53.766667 
                 3.4671474 
               
               
                 SEQ ID NO: 443) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 555: 
                 439 
                 UUUUCUUCUAGGAGGCUUUCAA 
                 GAAAGCCUCCUAGAAGAAAA 
                 78.3 
                 10.570872 
                 44.6 
                 5.3153865 
               
               
                 SEQ ID NO: 444) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 556: 
                 441 
                 UUUUUUCUUCUAGGAGGCUUUC 
                 AAGCCUCCUAGAAGAAAAAA 
                 121.76667 
                 14.653365 
                 85.266667 
                 6.4576397 
               
               
                 SEQ ID NO: 445) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 557: 
                 442 
                 UUUUUUUCUUCUAGGAGGCUUU 
                 AGCCUCCUAGAAGAAAAAAA 
                 106.1 
                 6.0135957 
                 77.6 
                 6.3846169 
               
               
                 SEQ ID NO: 446) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 558: 
                 446 
                 UAGAAUUUUUUCUUCUAGGAGG 
                 UCCUAGAAGAAAAAAUUCUA 
                 46.6 
                 3.3171273 
                 28.766667 
                 5.028364 
               
               
                 SEQ ID NO: 447) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 59: 
                 
                 
                   454 
                 
                 
                   UGUUGAAGUAGAAUUUUUUCUU 
                 
                 
                   GAAAAAAUUCUACUUCAACA 
                 
                 
                   65.933333 
                 
                 
                   2.2407836 
                 
                 
                   23.666667 
                 
                 
                   2.8179977 
                 
               
               
                 
                   SEQ ID NO: 120) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 60: 
                 
                 
                   456 
                 
                 
                   UUUGUUGAAGUAGAAUUUUUUC 
                 
                 
                   AAAAAUUCUACUUCAACAAA 
                 
                 
                   56.2 
                 
                 
                   7.5883683 
                 
                 
                   25.533333 
                 
                 
                   2.3596139 
                 
               
               
                 
                   SEQ ID NO: 121) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 559: 
                 457 
                 UUUUGUUGAAGUAGAAUUUUUU 
                 AAAAUUCUACUUCAACAAAA 
                 82.3 
                 4.8809152 
                 52.966667 
                 0.9261629 
               
               
                 SEQ ID NO: 448) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 560: 
                 458 
                 UUUUUGUUGAAGUAGAAUUUUU 
                 AAAUUCUACUUCAACAAAAA 
                 88.933333 
                 7.7365654 
                 46.433333 
                 4.2230847 
               
               
                 SEQ ID NO: 449) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 561: 
                 459 
                 UUUUUUGUUGAAGUAGAAUUUU 
                 AAUUCUACUUCAACAAAAAA 
                 91.6 
                 5.0362023 
                 61.8 
                 4.2394968 
               
               
                 SEQ ID NO: 450) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 562: 
                 460 
                 UCUUUUUGUUGAAGUAGAAUUU 
                 AUUCUACUUCAACAAAAAGA 
                 84.7 
                 3.4122329 
                 86.4 
                 8.1283455 
               
               
                 SEQ ID NO: 451) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 61: 
                 
                 
                   464 
                 
                 
                   UUUCACUUUUUGUUGAAGUAGA 
                 
                 
                   UACUUCAACAAAAAGUGAAA 
                 
                 
                   56.166667 
                 
                 
                   2.7846803 
                 
                 
                   26.2 
                 
                 
                   0.7211103 
                 
               
               
                 
                   SEQ ID NO: 122) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 563: 
                 466 
                 UAUUUCACUUUUUGUUGAAGUA 
                 CUUCAACAAAAAGUGAAAUA 
                 82.2 
                 2.1126603 
                 70.066667 
                 1.5602706 
               
               
                 SEQ ID NO: 452) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 564: 
                 468 
                 UAUAUUUCACUUUUUGUUGAAG 
                 UCAACAAAAAGUGAAAUAUA 
                 74.533333 
                 4.5961336 
                 38.733333 
                 0.8373238 
               
               
                 SEQ ID NO: 453) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 33: 
                 
                 
                   474 
                 
                 
                   UUUCUAAAUAUUUCACUUUUUG 
                 
                 
                   AAAAGUGAAAUAUUUAGAAA 
                 
                 
                   52.933333 
                 
                 
                   1.7854349 
                 
                 
                   24.066667 
                 
                 
                   0.9404491 
                 
               
               
                 
                   SEQ ID NO: 94) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 565: 
                 475 
                 UCUUCUAAAUAUUUCACUUUUU 
                 AAAGUGAAAUAUUUAGAAGA 
                 76 
                 2.0207259 
                 41.866667 
                 1.7265894 
               
               
                 SEQ ID NO: 454) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 34: 
                 
                 
                   488 
                 
                 
                   UUUAGUUAGUUGCUCUUCUAAA 
                 
                 
                   UAGAAGAGCAACUAACUAAA 
                 
                 
                   48.666667 
                 
                 
                   1.5070206 
                 
                 
                   20.033333 
                 
                 
                   0.5238745 
                 
               
               
                 
                   SEQ ID NO: 95) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 566: 
                 495 
                 UAAUUAAGUUAGUUAGUUGCUC 
                 GCAACUAACUAACUUAAUUA 
                 63.9 
                 2.7495454 
                 31.933333 
                 1.8187297 
               
               
                 SEQ ID NO: 455) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 567: 
                 501 
                 UAUUUUGAAUUAAGUUAGUUAG 
                 AACUAACUUAAUUCAAAAUA 
                 98.266667 
                 0.9171211 
                 75.5 
                 2.4826062 
               
               
                 SEQ ID NO: 456) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 568: 
                 502 
                 UGAUUUUGAAUUAAGUUAGUUA 
                 ACUAACUUAAUUCAAAAUCA 
                 87.2 
                 2.4269322 
                 48.4 
                 3.4655447 
               
               
                 SEQ ID NO: 457) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 569: 
                 505 
                 UGUUGAUUUUGAAUUAAGUUAG 
                 AACUUAAUUCAAAAUCAACA 
                 102.56667 
                 5.7623298 
                 71.733333 
                 2.9979623 
               
               
                 SEQ ID NO: 458) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 7: 
                 
                 
                   544 
                 
                 
                   UUUUUAAGUGAAGUUACUUCUG 
                 
                 
                   GAAGUAACUUCACUUAAAAA 
                 
                 
                   58.9 
                 
                 
                   2.6388129 
                 
                 
                   24.466667 
                 
                 
                   1.8123036 
                 
               
               
                 
                   SEQ ID NO: 68) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 36: 
                 
                 
                   572 
                 
                 
                   UAUGCUAUUAUCUUGUUUUUCU 
                 
                 
                   AAAAACAAGAUAAUAGCAUA 
                 
                 
                   48.633333 
                 
                 
                   3.2712553 
                 
                 
                   17.4 
                 
                 
                   2.1221059 
                 
               
               
                 
                   SEQ ID NO: 97) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 570: 
                 633 
                 UUUGACUAUGCUGUUGGUUUAA 
                 AAACCAACAGCAUAGUCAAA 
                 103.5 
                 3.1432467 
                 68.833333 
                 1.3420548 
               
               
                 SEQ ID NO: 459) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 571: 
                 634 
                 UUUUGACUAUGCUGUUGGUUUA 
                 AACCAACAGCAUAGUCAAAA 
                 97.166667 
                 8.5341145 
                 83.366667 
                 8.2561761 
               
               
                 SEQ ID NO: 460) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 572: 
                 636 
                 UUAUUUGACUAUGCUGUUGGUU 
                 CCAACAGCAUAGUCAAAUAA 
                 91.3 
                 10.1 
                 58.6 
                 4.0648903 
               
               
                 SEQ ID NO: 461) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 573: 
                 639 
                 UUUUUAUUUGACUAUGCUGUUG 
                 ACAGCAUAGUCAAAUAAAAA 
                 101.53333 
                 9.5729364 
                 47 
                 2.2854613 
               
               
                 SEQ ID NO: 462) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 574: 
                 642 
                 UUUCUUUUAUUUGACUAUGCUG 
                 GCAUAGUCAAAUAAAAGAAA 
                 124.33333 
                 20.129277 
                 45.466667 
                 2.8759539 
               
               
                 SEQ ID NO: 463) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 575: 
                 645 
                 UUAUUUCUUUUAUUUGACUAUG 
                 UAGUCAAAUAAAAGAAAUAA 
                 107.9 
                 8.2099533 
                 49.3 
                 4.2770706 
               
               
                 SEQ ID NO: 464) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 576: 
                 646 
                 UCUAUUUCUUUUAUUUGACUAU 
                 AGUCAAAUAAAAGAAAUAGA 
                 112.63333 
                 5.1872707 
                 56.2 
                 10.759337 
               
               
                 SEQ ID NO: 465) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 577: 
                 649 
                 UUUUCUAUUUCUUUUAUUUGAC 
                 CAAAUAAAAGAAAUAGAAAA 
                 73.1 
                 7.7323994 
                 38.733333 
                 2.9384425 
               
               
                 SEQ ID NO: 466) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 578: 
                 651 
                 UAUUUUCUAUUUCUUUUAUUUG 
                 AAUAAAAGAAAUAGAAAAUA 
                 75.3 
                 2.0952327 
                 43.2 
                 1.4977761 
               
               
                 SEQ ID NO: 467) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 579: 
                 654 
                 UCUGAUUUUCUAUUUCUUUUAU 
                 AAAAGAAAUAGAAAAUCAGA 
                 89 
                 6.4779112 
                 56.166667 
                 4.9670022 
               
               
                 SEQ ID NO: 468) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 580: 
                 691 
                 UAAAUUUCUGUGGGUUCUUGAA 
                 CAAGAACCCACAGAAAUUUA 
                 97.466667 
                 9.619136 
                 57.9 
                 6.6161419 
               
               
                 SEQ ID NO: 469) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 38: 
                 
                 
                   694 
                 
                 
                   UGAGAAAUUUCUGUGGGUUCUU 
                 
                 
                   GAACCCACAGAAAUUUCUCA 
                 
                 
                   60.533333 
                 
                 
                   4.4212869 
                 
                 
                   26.566667 
                 
                 
                   5.5798248 
                 
               
               
                 
                   SEQ ID NO: 99) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 8: 
                 
                 
                   701 
                 
                 
                   UGAAGAUAGAGAAAUUUCUGUG 
                 
                 
                   CAGAAAUUUCUCUAUCUUCA 
                 
                 
                   60.966667 
                 
                 
                   2.2063041 
                 
                 
                   23.066667 
                 
                 
                   1.4110674 
                 
               
               
                 
                   SEQ ID NO: 69) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 581: 
                 702 
                 UGGAAGAUAGAGAAAUUUCUGU 
                 AGAAAUUUCUCUAUCUUCCA 
                 75.333333 
                 1.8223916 
                 42.3 
                 2.0404248 
               
               
                 SEQ ID NO: 470) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 582: 
                 762 
                 UUUUUACAUUUCUUAUUUCAUU 
                 UGAAAUAAGAAAUGUAAAAA 
                 71.6 
                 1.0440307 
                 42.466667 
                 7.7203915 
               
               
                 SEQ ID NO: 471) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 583: 
                 763 
                 UGUUUUACAUUUCUUAUUUCAU 
                 GAAAUAAGAAAUGUAAAACA 
                 60.266667 
                 8.2049443 
                 28.2 
                 1.6802778 
               
               
                 SEQ ID NO: 472) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 584: 
                 765 
                 UAUGUUUUACAUUUCUUAUUUC 
                 AAUAAGAAAUGUAAAACAUA 
                 113.93333 
                 6.6217655 
                 71.2 
                 6.512552 
               
               
                 SEQ ID NO: 473) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 585: 
                 768 
                 UAUCAUGUUUUACAUUUCUUAU 
                 AAGAAAUGUAAAACAUGAUA 
                 114.4 
                 15.162124 
                 84.766667 
                 4.7178149 
               
               
                 SEQ ID NO: 474) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 586: 
                 862 
                 UCAUGAAAAACUUGAGAGUUGC 
                 AACUCUCAAGUUUUUCAUGA 
                 94.3 
                 16.67643 
                 44.8 
                 4.9923274 
               
               
                 SEQ ID NO: 475) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 587: 
                 932 
                 UAAGUUUUGUGAUCCAUCUAUU 
                 UAGAUGGAUCACAAAACUUA 
                 61.733333 
                 0.6741249 
                 31.766667 
                 0.6119187 
               
               
                 SEQ ID NO: 476) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 588: 
                 939 
                 UUUCAUUGAAGUUUUGUGAUCC 
                 AUCACAAAACUUCAAUGAAA 
                 78.2 
                 4.1932485 
                 42.7 
                 2.5534291 
               
               
                 SEQ ID NO: 477) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 589: 
                 941 
                 UGUUUCAUUGAAGUUUUGUGAU 
                 CACAAAACUUCAAUGAAACA 
                 89.466667 
                 3.2297231 
                 67.466667 
                 1.0898522 
               
               
                 SEQ ID NO: 478) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 590: 
                 942 
                 UCGUUUCAUUGAAGUUUUGUGA 
                 ACAAAACUUCAAUGAAACGA 
                 85.566667 
                 4.6048284 
                 83.266667 
                 1.6374099 
               
               
                 SEQ ID NO: 479) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 591: 
                 957 
                 UUUUGUAGUUCUCCCACGUUUC 
                 AACGUGGGAGAACUACAAAA 
                 70.866667 
                 2.5201411 
                 56.233333 
                 2.1073944 
               
               
                 SEQ ID NO: 480) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 592: 
                 958 
                 UAUUUGUAGUUCUCCCACGUUU 
                 ACGUGGGAGAACUACAAAUA 
                 69.2 
                 0.6350853 
                 53.933333 
                 1.7071744 
               
               
                 SEQ ID NO: 481) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 593: 
                 959 
                 UUAUUUGUAGUUCUCCCACGUU 
                 CGUGGGAGAACUACAAAUAA 
                 71.3 
                 1.0535654 
                 51.033333 
                 0.7310571 
               
               
                 SEQ ID NO: 482) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 594: 
                 1011 
                 UGUAUAUCUUCUCUAGGCCCAA 
                 GGGCCUAGAGAAGAUAUACA 
                 80.066667 
                 3.3152845 
                 56.766667 
                 1.0898522 
               
               
                 SEQ ID NO: 483) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 595: 
                 1012 
                 UAGUAUAUCUUCUCUAGGCCCA 
                 GGCCUAGAGAAGAUAUACUA 
                 70.333333 
                 14.174194 
                 52.633333 
                 5.1450084 
               
               
                 SEQ ID NO: 484) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 43: 
                 
                   1034 
                 
                 
                   UUAAUUAGAUUGCUUCACUAUG 
                 
                 
                   UAGUGAAGCAAUCUAAUUAA 
                 
                 
                   52.6 
                 
                 
                   1.1676187 
                 
                 
                   21.833333 
                 
                 
                   4.547649 
                 
               
               
                 
                   SEQ ID NO: 304) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 596: 
                 1072 
                 UUGUUGUCUUUCCAGUCUUCCA 
                 GAAGACUGGAAAGACAACAA 
                 87.7 
                 1.1135529 
                 54.8 
                 1.7521415 
               
               
                 SEQ ID NO: 485) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 597: 
                 1075 
                 UGUUUGUUGUCUUUCCAGUCUU 
                 GACUGGAAAGACAACAAACA 
                 101.76667 
                 2.8497563 
                 81.633333 
                 3.0333333 
               
               
                 SEQ ID NO: 486) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 598: 
                 1077 
                 UAUGUUUGUUGUCUUUCCAGUC 
                 CUGGAAAGACAACAAACAUA 
                 87.033333 
                 1.8113838 
                 56.7 
                 1.8027756 
               
               
                 SEQ ID NO: 487) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 10: 
                 
                 
                   1079 
                 
                 
                   UUAAUGUUUGUUGUCUUUCCAG 
                 
                 
                   GGAAAGACAACAAACAUUAA 
                 
                 
                   55.666667 
                 
                 
                   1.4449145 
                 
                 
                   25.4 
                 
                 
                   0.8082904 
                 
               
               
                 
                   SEQ ID NO: 71) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 45: 
                 
                 
                   1082 
                 
                 
                   UAUAUAAUGUUUGUUGUCUUUC 
                 
                 
                   AAGACAACAAACAUUAUAUA 
                 
                 
                   45.233333 
                 
                 
                   2.2556103 
                 
                 
                   17.866667 
                 
                 
                   1.0397649 
                 
               
               
                 
                   SEQ ID NO: 106) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 599: 
                 1083 
                 UAAUAUAAUGUUUGUUGUCUUU 
                 AGACAACAAACAUUAUAUUA 
                 84.566667 
                 5.500404 
                 50.2 
                 2.8448784 
               
               
                 SEQ ID NO: 488) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 600: 
                 1086 
                 UUUCAAUAAAUGUUUGUUGUC 
                 CAACAAACAUUAUAUUGAAA 
                 69.1266667 
                 4.9599507 
                 31.766667 
                 0.6064468 
               
               
                 SEQ ID NO: 489) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 601: 
                 1088 
                 UUAUUCAAUAUAAUGUUUGUUG 
                 ACAAACAUUAUAUUGAAUAA 
                 58.4 
                 3.1749016 
                 31.366667 
                 0.8819171 
               
               
                 SEQ ID NO: 490) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 602: 
                 1089 
                 UAUAUUCAAUAUAAUGUUUGUU 
                 CAAACAUUAUAUUGAAUAUA 
                 84.5 
                 4.2524503 
                 56.7 
                 2.1221059 
               
               
                 SEQ ID NO: 491) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 603: 
                 1093 
                 UAAGAAUAUUCAAUAUAAUGUU 
                 CAUUAUAUUGAAUAUUCUUA 
                 84.866667 
                 1.3245544 
                 70.366667 
                 1.3980145 
               
               
                 SEQ ID NO: 492) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 
                   (SEQ ID NO: 46: 
                 
                 
                   1094 
                 
                 
                   UAAAGAAUAUUCAAUAUAAUGU 
                 
                 
                   AUUAUAUUGAAUAUUCUUUA 
                 
                 
                   49.7 
                 
                 
                   1.569501 
                 
                 
                   25.3 
                 
                 
                   1.3316656 
                 
               
               
                 
                   SEQ ID NO: 107) 
                 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 604: 
                 1097 
                 UUAAAAAGAAUAUUCAAUAUAA 
                 AUAUUGAAUAUUCUUUUUAA 
                 64.666667 
                 0.7535103 
                 43.7 
                 12.219247 
               
               
                 SEQ ID NO: 493) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 605: 
                 1098 
                 UGUAAAAAGAAUAUUCAAUAUA 
                 UAUUGAAUAUUCUUUUUACA 
                 60.033333 
                 3.0179095 
                 35.566667 
                 1.0088497 
               
               
                 SEQ ID NO: 494) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 606: 
                 1120 
                 UAGUUGGUUUCGUGAUUUCCCA 
                 GGAAAUCACGAAACCAACUA 
                 67.666667 
                 2.4009257 
                 61.2 
                 1.7925773 
               
               
                 SEQ ID NO: 495) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 607: 
                 1179 
                 UUUUGUUUUCCGGGAUUGCAUU 
                 UGCAAUCCCGGAAAACAAAA 
                 95.633333 
                 5.8356186 
                 75.133333 
                 6.4957251 
               
               
                 SEQ ID NO: 496) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 608: 
                 1180 
                 UCUUUGUUUUCCGGGAUUGCAU 
                 GCAAUCCCGGAAAACAAAGA 
                 112.66667 
                 4.7301633 
                 89.033333 
                 7.1884939 
               
               
                 SEQ ID NO: 497) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 609: 
                 1186 
                 UCCAAAUCUUUGUUUUCCGGGA 
                 CCGGAAAACAAAGAUUUGGA 
                 108.9 
                 3.5360053 
                 68.2 
                 3.5341194 
               
               
                 SEQ ID NO: 498) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 610: 
                 1196 
                 UGUAGAAAACACCAAAUCUUUG 
                 AAGAUUUGGUGUUUUCUACA 
                 83.866667 
                 1.8675593 
                 53.8 
                 2.0502032 
               
               
                 SEQ ID NO: 499) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 611: 
                 1199 
                 UCAAGUAGAAAACACCAAAUCU 
                 AUUUGGUGUUUUCUACUUGA 
                 99.566667 
                 1.3617799 
                 50.4 
                 3.9208843 
               
               
                 SEQ ID NO: 500) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 612: 
                 1210 
                 UCUUUGUGAUCCCAAGUAGAAA 
                 UCUACUUGGGAUCACAAAGA 
                 96.066667 
                 2.8368605 
                 65.5 
                 0.9291573 
               
               
                 SEQ ID NO: 501) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 613: 
                 1216 
                 UCUUUUGCUUUGUGAUCCCAAG 
                 UGGGAUCACAAAGCAAAAGA 
                 96.733333 
                 4.2451279 
                 74.533333 
                 5.7649323 
               
               
                 SEQ ID NO: 502) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 614: 
                 1282 
                 UUGUUUUCUCCACACUCAUCAU 
                 GAUGAGUGUGGAGAAAACAA 
                 100.1 
                 8.2002032 
                 69.433333 
                 2.8695722 
               
               
                 SEQ ID NO: 503) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 615: 
                 1283 
                 UUUGUUUUCUCCACACUCAUCA 
                 AUGAGUGUGGAGAAAACAAA 
                 96.766667 
                 5.2122718 
                 61.5 
                 3.3045423 
               
               
                 SEQ ID NO: 504) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 616: 
                 1284 
                 UGUUGUUUUCUCCACACUCAUC 
                 UGAGUGUGGAGAAAACAACA 
                 110.1 
                 4.0016663 
                 68.833333 
                 4.8670091 
               
               
                 SEQ ID NO: 505) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 617: 
                 1291 
                 UCAUUUAGGUUGUUUUCUCCAC 
                 GGAGAAAACAACCUAAAUGA 
                 96.566667 
                 6.0000926 
                 55.833333 
                 8.5958 
               
               
                 SEQ ID NO: 506) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 618: 
                 1295 
                 UUUACCAUUUAGGUUGUUUUCU 
                 AAAACAACCUAAAUGGUAAA 
                 118.76667 
                 3.4594476 
                 95.5 
                 17.707155 
               
               
                 SEQ ID NO: 507) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 619: 
                 1296 
                 UUUUACCAUUUAGGUUGUUUUC 
                 AAACAACCUAAAUGGUAAAA 
                 109.8 
                 2.7495454 
                 80.233333 
                 5.0273695 
               
               
                 SEQ ID NO: 508) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 620: 
                 1297 
                 UAUUUACCAUUUAGGUUGUUUU 
                 AACAACCUAAAUGGUAAAUA 
                 103.26667 
                 3.2620716 
                 68.366667 
                 9.5202124 
               
               
                 SEQ ID NO: 509) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 621: 
                 1299 
                 UAUAUUUACCAUUUAGGUUGUU 
                 CAACCUAAAUGGUAAAUAUA 
                 91.366667 
                 3.2199034 
                 47.566667 
                 5.1239091 
               
               
                 SEQ ID NO: 510) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 622: 
                 1303 
                 UUGUUAUAUUUACCAUUUAGGU 
                 CUAAAUGGUAAAUAUAACAA 
                 108.16667 
                 13.339832 
                 76.766667 
                 5.7391443 
               
               
                 SEQ ID NO: 511) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 623: 
                 1305 
                 UUUUGUUAUAUUUACCAUUUAG 
                 AAAUGGUAAAUAUAACAAAA 
                 75.466667 
                 5.3868152 
                 41.533333 
                 6.1723397 
               
               
                 SEQ ID NO: 512) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 624: 
                 1306 
                 UGUUUGUUAUAUUUACCAUUUA 
                 AAUGGUAAAUAUAACAAACA 
                 99.033333 
                 9.7886556 
                 81.766667 
                 2.7412487 
               
               
                 SEQ ID NO: 513) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 625: 
                 1376 
                 UGAGUAUAACCUUCCAUUUUGA 
                 AAAAUGGAAGGUUAUACUCA 
                 75.1 
                 2.0305993 
                 56.466667 
                 4.4175156 
               
               
                 SEQ ID NO: 514) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 626: 
                 1380 
                 UUAUAGAGUAUAACCUUCCAUU 
                 UGGAAGGUUAUACUCUAUAA 
                 75.933333 
                 17.922456 
                 31.133333 
                 3.5025388 
               
               
                 SEQ ID NO: 515) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 627: 
                 1384 
                 UAUUUUAUAGAGUAUAACCUUC 
                 AGGUUAUACUCUAUAAAAUA 
                 64.533333 
                 2.4767811 
                 46.9 
                 2.570992 
               
               
                 SEQ ID NO: 516) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 628: 
                 1388 
                 UGUUGAUUUUAUAGAGUAUAAC 
                 UAUACUCUAUAAAAUCAACA 
                 102 
                 13.360514 
                 98.333333 
                 9.7813314 
               
               
                 SEQ ID NO: 517) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 629: 
                 1394 
                 UAUUUUGGUUGAUUUUAUAGAG 
                 CUAUAAAAUCAACCAAAAUA 
                 69.833333 
                 6.5973058 
                 58.766667 
                 1.449521 
               
               
                 SEQ ID NO: 518) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 630: 
                 1426 
                 UCAAAGCUUUCUGAAUCUGUUG 
                 ACAGAUUCAGAAAGCUUUGA 
                 62.366667 
                 1.6333333 
                 46.1 
                 1.5 
               
               
                 SEQ ID NO: 519) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 631: 
                 1434 
                 UAGUUCAUUCAAAGCUUUCUGA 
                 AGAAAGCUUUGAAUGAACUA 
                 92.833333 
                 3.9295179 
                 54.666667 
                 3.9252742 
               
               
                 SEQ ID NO: 520) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 632: 
                 1447 
                 UUUAAAUUUGCCUCAGUUCAUU 
                 UGAACUGAGGCAAAUUUAAA 
                 66.866667 
                 2.5260861 
                 29.566667 
                 1.3119112 
               
               
                 SEQ ID NO: 521) 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 633: 
                 1448 
                 UUUUAAAUUUGCCUCAGUUCAU 
                 GAACUGAGGCAAAUUUAAAA 
                 66.933333 
                 3.5295577 
                 30.566667 
                 1.2333333 
               
               
                 SEQ ID NO: 522) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Exemplary Sequences and Their Calculated Absolute 
               
               
                 IC50 Values by Dose Response in Primary Hepatocytes 
               
            
           
           
               
               
               
            
               
                   
                 Free uptake in primary 
                 Free uptake in primary 
               
               
                   
                 cynomolgus hepatocytes (PCH) 
                 human hepatocytes (PHH) 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Log 
                 Absolute 
                 Log 
                 Absolute 
               
               
                 SEQ ID NOS: 
                 (concentration) 
                 IC50 (nM) 
                 (concentration) 
                 IC50 (nM) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 (SEQ ID NO: 278: SEQ ID NO: 134) 
                 −0.284 
                 0.52 
                 0.160 
                 1.45 
               
               
                 (SEQ ID NO: 19: SEQ ID NO: 80) 
                 0.135 
                 1.36 
                 0.469 
                 2.94 
               
               
                 (SEQ ID NO: 24: SEQ ID NO: 85) 
                 0.057 
                 1.14 
                 0.652 
                 4.49 
               
               
                 (SEQ ID NO: 30: SEQ ID NO: 91) 
                 0.111 
                 1.29 
                 0.574 
                 3.75 
               
               
                 (SEQ ID NO: 31: SEQ ID NO: 92) 
                 −0.064 
                 0.86 
                 0.282 
                 1.91 
               
               
                 (SEQ ID NO: 62: SEQ ID NO: 123) 
                 0.201 
                 1.59 
                 0.253 
                 1.79 
               
               
                 (SEQ ID NO: 9: SEQ ID NO: 70) 
                 −0.284 
                 0.52 
                 −0.152 
                 0.71 
               
               
                 (SEQ ID NO: 15: SEQ ID NO: 76) 
                 −0.355 
                 0.44 
                 −0.429 
                 0.37 
               
               
                 (SEQ ID NO: 2: SEQ ID NO: 63) 
                 0.411 
                 2.58 
                 0.050 
                 1.12 
               
               
                 (SEQ ID NO: 17: SEQ ID NO: 78) 
                 0.039 
                 1.09 
                 0.204 
                 1.60 
               
               
                 (SEQ ID NO: 20: SEQ ID NO: 81) 
                 0.126 
                 1.34 
                 0.529 
                 3.38 
               
               
                 (SEQ ID NO: 21: SEQ ID NO: 82) 
                 0.119 
                 1.32 
                 0.432 
                 2.71 
               
               
                 (SEQ ID NO: 22: SEQ ID NO: 83) 
                 0.050 
                 1.12 
                 0.300 
                 2.00 
               
               
                 (SEQ ID NO: 23: SEQ ID NO: 84) 
                 0.539 
                 3.46 
                 0.218 
                 1.65 
               
               
                 (SEQ ID NO: 530: SEQ ID NO: 419) 
                 0.741 
                 5.51 
                 0.758 
                 5.73 
               
               
                 (SEQ ID NO: 25: SEQ ID NO: 86) 
                 0.137 
                 1.37 
                 0.436 
                 2.73 
               
               
                 (SEQ ID NO: 4: SEQ ID NO: 65) 
                 0.500 
                 3.16 
                 0.550 
                 3.55 
               
               
                 (SEQ ID NO: 26: SEQ ID NO: 87) 
                 0.485 
                 3.05 
                 0.427 
                 2.67 
               
               
                 (SEQ ID NO: 28: SEQ ID NO: 89) 
                 −0.381 
                 0.42 
                 0.202 
                 1.59 
               
               
                 (SEQ ID NO: 29: SEQ ID NO: 90) 
                 0.137 
                 1.37 
                 0.509 
                 3.23 
               
               
                 (SEQ ID NO: 5: SEQ ID NO: 66) 
                 0.214 
                 1.64 
                 0.440 
                 2.75 
               
               
                 (SEQ ID NO: 558: SEQ ID NO: 447) 
                 0.413 
                 2.59 
                 0.396 
                 2.49 
               
               
                 (SEQ ID NO: 60: SEQ ID NO: 121) 
                 0.491 
                 3.10 
                 0.468 
                 2.94 
               
               
                 (SEQ ID NO: 61: SEQ ID NO: 122) 
                 0.181 
                 1.52 
                 0.369 
                 2.34 
               
               
                 (SEQ ID NO: 34: SEQ ID NO: 95) 
                 −0.093 
                 0.81 
                 −0.077 
                 0.84 
               
               
                 (SEQ ID NO: 7: SEQ ID NO: 68) 
                 0.288 
                 1.94 
                 −0.230 
                 0.59 
               
               
                 (SEQ ID NO: 36: SEQ ID NO: 97) 
                 −0.015 
                 0.97 
                 −0.187 
                 0.65 
               
               
                 (SEQ ID NO: 43: SEQ ID NO: 104) 
                 −0.346 
                 0.45 
                 −0.238 
                 0.58 
               
               
                 (SEQ ID NO: 10: SEQ ID NO: 71) 
                 −0.252 
                 0.56 
                 −0.017 
                 0.96 
               
               
                 (SEQ ID NO: 45: SEQ ID NO: 106) 
                 −0.268 
                 0.54 
                 −0.116 
                 0.77 
               
               
                 (SEQ ID NO: 46: SEQ ID NO: 107) 
                 −0.003 
                 0.99 
                 0.519 
                 3.31 
               
               
                 (SEQ ID NO: 18: SEQ ID NO: 79) 
                 −0.151 
                 0.71 
                 0.181 
                 1.52 
               
               
                 (SEQ ID NO: 296: SEQ ID NO: 152) 
                 0.418 
                 2.62 
                 0.821 
                 6.62 
               
               
                 (SEQ ID NO: 11: SEQ ID NO: 72) 
                 0.055 
                 1.13 
                 0.091 
                 1.23 
               
               
                 (SEQ ID NO: 278: SEQ ID NO: 134) 
                 −0.284 
                 0.52 
                 0.160 
                 1.45 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Exemplary Sequences of the Present Application 
               
               
                 and Their in vivo Potency in Silencing Human Angptl3 mRNA 
               
            
           
           
               
               
               
               
               
            
               
                 Guide 
                   
                 Passenger 
                   
                 % of gene 
               
               
                 Strand 
                   
                 Strand 
                   
                 remaining at 
               
               
                 SEQ 
                 Guide strand 
                 SEQ 
                 Passenger strand  
                 0.5 mg/kg 
               
            
           
           
               
               
               
               
               
               
            
               
                 ID NOs 
                 sequence (5′-3′) 
                 ID NOs 
                 sequence (5′-3′) 
                 Mean 
                 SD 
               
               
                   
               
               
                  18 
                 UAAAUCUUGAUUUUGGCUCUGG 
                  79 
                 AGAGCCAAAAUCAAGAUUUA 
                 74.39 
                  9.502 
               
               
                   
               
               
                 278 
                 UUAGCAAAUCUUGAUUUUGGCU 
                 134 
                 CCAAAAUCAAGAUUUGCUAA 
                 73.8 
                  9.193 
               
               
                   
               
               
                  19 
                 UCAUAGCAAAUCUUGAUUUUGG 
                  80 
                 AAAAUCAAGAUUUGCUAUGA 
                 60.27 
                  7.703 
               
               
                   
               
               
                 296 
                 UGACUGAUCAAAUAUGUUGAGU 
                 152 
                 UCAACAUAUUUGAUCAGUCA 
                 84.18 
                  9.553 
               
               
                   
               
               
                 296 
                 UGACUGAUCAAAUAUGUUGAGU 
                 152 
                 UCAACAUAUUUGAUCAGUCA 
                 75.23 
                 17.3 
               
               
                   
               
               
                  24 
                 UGAUAGAUCAUAAAAAGACUGA 
                  85 
                 AGUCUUUUUAUGAUCUAUCA 
                 58.71 
                 11.97 
               
               
                   
               
               
                  30 
                 UUUAAGUUAGUUAGUUGCUCUU 
                  91 
                 GAGCAACUAACUAACUUAAA 
                 53.96 
                  6.406 
               
               
                   
               
               
                  31 
                 UAUUAAGUUAGUUAGUUGCUCU 
                  92 
                 AACAGCAUAGUCAAAUAAAA 
                 51 
                 17.42 
               
               
                   
               
               
                  62 
                 UUUUAUUUGACUAUGCUGUUGG 
                 123 
                 AACAGCAUAGUCAAAUAAAA 
                 52.65 
                 13.27 
               
               
                   
               
               
                  62 
                 UUUUAUUUGACUAUGCUGUUGG 
                 123 
                 AACAGCAUAGUCAAAUAAAA 
                 68.9 
                 10.23 
               
               
                   
               
               
                   9 
                 UGAAAAACUUGAGAGUUGCUGG 
                  70 
                 AGCAACUCUCAAGUUUUUCA 
                 82.52 
                 12.94 
               
               
                   
               
               
                  11 
                 UGUAUAACCUUCCAUUUUGAGA 
                  72 
                 UCAAAAUGGAAGGUUAUACA 
                 76.28 
                  4.298 
               
               
                   
               
               
                  15 
                 UAUAAAAAGAAGGAGCUUAAUU 
                  76 
                 UUAAGCUCCUUCUUUUUAUA 
                 79.86 
                 12.09 
               
               
                   
               
               
                   2 
                 UCAAUAAAAAGAAGGAGCUUAA 
                  63 
                 AAGCUCCUUCUUUUUAUUGA 
                 63.26 
                  9.028 
               
               
                   
               
               
                  17 
                 UAAAUAACUAGAGGAACAAUAA 
                  78 
                 AUUGUUCCUCUAGUUAUUUA 
                 65.58 
                 10.09 
               
               
                   
               
               
                  20 
                 UUUGAUUUUGGCUCUGGAGAUA 
                  81 
                 UCUCCAGAGCCAAAAUCAAA 
                 53.58 
                 10.27 
               
               
                   
               
               
                  21 
                 UAUCGUCUAACAUAGCAAAUCU 
                  82 
                 AUUUGCUAUGUUAGACGAUA 
                 75.71 
                  4.106 
               
               
                   
               
               
                  22 
                 UAUUUUUACAUCGUCUAACAUA 
                  83 
                 UGUUAGACGAUGUAAAAAUA 
                 70.01 
                 10.57 
               
               
                   
               
               
                  23 
                 UAAAAUUUUUACAUCGUCUAAC 
                  84 
                 UAGACGAUGUAAAAAUUUUA 
                 51.07 
                  4.74 
               
               
                   
               
               
                 530 
                 UUAAAAUUUUUACAUCGUCUAA 
                 419 
                 AGACGAUGUAAAAAUUUUAA 
                 60.36 
                 13.02 
               
               
                   
               
               
                  25 
                 UUAAAAAGACUGAUCAAAUAUG 
                  86 
                 UAUUUGAUCAGUCUUUUUAA 
                 56.46 
                  4.632 
               
               
                   
               
               
                   4 
                 UAUAAAAAGACUGAUCAAAUAU 
                  65 
                 AUUUGAUCAGUCUUUUUAUA 
                 52.22 
                  5.367 
               
               
                   
               
               
                  26 
                 UAUAGAUCAUAAAAAGACUGAU 
                  87 
                 CAGUCUUUUUAUGAUCUAUA 
                 66.88 
                 13.51 
               
               
                   
               
               
                  28 
                 UUUUAUAUGUAGUUCUUCUCAG 
                  89 
                 GAGAAGAACUACAUAUAAAA 
                 60.78 
                 17.33 
               
               
                   
               
               
                  29 
                 UAUUUUUGACUUGUAGUUUAUA 
                  90 
                 UAAACUACAAGUCAAAAAUA 
                 61.32 
                 17.12 
               
               
                   
               
               
                   5 
                 UGACAUAUUCUUUACCUCUUCA 
                  66 
                 AAGAGGUAAAGAAUAUGUCA 
                 48.7 
                  5.69 
               
               
                   
               
               
                 558 
                 UAGAAUUUUUUCUUCUAGGAGG 
                 447 
                 UCCUAGAAGAAAAAAUUCUA 
                 49.84 
                 10.66 
               
               
                   
               
               
                  60 
                 UUUGUUGAAGUAGAAUUUUUUC 
                 121 
                 AAAAAUUCUACUUCAACAAA 
                 43.72 
                  4.574 
               
               
                   
               
               
                  61 
                 UUUCACUUUUUGUUGAAGUAGA 
                 122 
                 UACUUCAACAAAAAGUGAAA 
                 47.28 
                 10.15 
               
               
                   
               
               
                  34 
                 UUUAGUUAGUUGCUCUUCUAAA 
                  95 
                 UAGAAGAGCAACUAACUAAA 
                 51.34 
                  8.448 
               
               
                   
               
               
                   7 
                 UUUUUAAGUGAAGUUACUUCUG 
                  68 
                 GAAGUAACUUCACUUAAAAA 
                 54.32 
                 14.11 
               
               
                   
               
               
                  36 
                 UAUGCUAUUAUCUUGUUUUUCU 
                  97 
                 AAAAACAAGAUAAUAGCAUA 
                 60.18 
                 23.03 
               
               
                   
               
               
                  43 
                 UUAAUUAGAUUGCUUCACUAUG 
                 104 
                 UAGUGAAGCAAUCUAAUUAA 
                 53.12 
                  7.828 
               
               
                   
               
               
                  10 
                 UUAAUGUUUGUUGUCUUUCCAG 
                  71 
                 GGAAAGACAACAAACAUUAA 
                 85.52 
                 25.14 
               
               
                   
               
               
                  45 
                 UAUAUAAUGUUUGUUGUCUUUC 
                 106 
                 AAGACAACAAACAUUAUAUA 
                 43.89 
                  6.124 
               
               
                   
               
               
                  46 
                 UAAAGAAUAUUCAAUAUAAUGU 
                 107 
                 AUUAUAUUGAAUAUUCUUUA 
                 48.36 
                  6.407 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Exemplary Sequences of the Present Disclosures and 
               
               
                 Their in vivo Dose Response in Silencing Human Angptl3 mRNA 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 % mRNA 
                 % mRNA 
                 % mRNA 
               
               
                 Guide 
                 Passenger 
                   
                   
                 remaining 
                 remaining 
                 remaining 
               
               
                 Strand 
                 Strand 
                   
                   
                 at 
                 at 
                 at 
               
               
                 SEQ 
                 SEQ 
                 Guide strand 
                 Passenger strand  
                 0.25 mg/kg 
                 0.5 mg/kg 
                 1 mg/kg 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 ID NOs 
                 ID NOs 
                 sequence (5′-3′) 
                 sequence (5′-3′) 
                 Mean 
                 SD 
                 Mean 
                 SD 
                 Mean 
                 SD 
               
               
                   
               
               
                  18 
                  79 
                 UAAAUCUUGAUUUUGGCUCUGG 
                 AGAGCCAAAAUCAAGAUUUA 
                  89.2 
                 14.4 
                 84.8 
                 13.6 
                 62.6 
                 10.6 
               
               
                   
               
               
                 278 
                 134 
                 UUAGCAAAUCUUGAUUUUGGCU 
                 CCAAAAUCAAGAUUUGCUAA 
                  81.24 
                 11.83 
                 72.4 
                  9.5 
                 53.9 
                  7.6 
               
               
                   
               
               
                  19 
                  80 
                 UCAUAGCAAAUCUUGAUUUUGG 
                 AAAAUCAAGAUUUGCUAUGA 
                  71.63 
                  8.30 
                 32.1 
                  7 3 
                 25.6 
                  9.0 
               
               
                   
               
               
                  48 
                 109 
                 UUUUACAUCGUCUAACAUAGCA 
                 CUAUGUUAGACGAUGUAAAA 
                  65.31 
                 25.23 
                 54.3 
                 16.1 
                 55.2 
                  5.5 
               
               
                   
               
               
                   3 
                  64 
                 UAAAUUUUUACAUCGUCUAACA 
                 UUAGACGAUGUAAAAAUUUA 
                  81.92 
                 14.35 
                 61.7 
                  6.1 
                 57.1 
                  8.2 
               
               
                   
               
               
                 296 
                 152 
                 UGACUGAUCAAAUAUGUUGAGU 
                 UCAACAUAUUUGAUCAGUCA 
                  94.31 
                 25.87 
                 76.6 
                 13.1 
                 60.9 
                 12.5 
               
               
                   
               
               
                  24 
                  85 
                 UGAUAGAUCAUAAAAAGACUGA 
                 AGUCUUUUUAUGAUCUAUCA 
                  70.19 
                 16.52 
                 46.1 
                  5.6 
                 39.5 
                  7.1 
               
               
                   
               
               
                  54 
                 115 
                 UUUAUAUGUAGUUCUUCUCAGU 
                 UGAGAAGAACUACAUAUAAA 
                  51.01 
                 11.37 
                 56.7 
                  9.7 
                 57.1 
                  9.5 
               
               
                   
               
               
                  56 
                 117 
                 UUUGAGUUGAGUUCAAGUGACA 
                 UCACUUGAACUCAACUCAAA 
                  77.69 
                 20.94 
                 60.0 
                 12.3 
                 48.8 
                  5.0 
               
               
                   
               
               
                 316 
                 172 
                 UAAUUUUUUCUUCUAGGAGGCU 
                 CCUCCUAGAAGAAAAAAUUA 
                  78.73 
                 14.30 
                 84.0 
                 22.3 
                 74.8 
                  9.4 
               
               
                   
               
               
                  57 
                 118 
                 UAAGUUAGUUAGUUGCUCUUCU 
                 AAGAGCAACUAACUAACUUA 
                  84.54 
                 17.77 
                 62.6 
                 17.5 
                 46.7 
                 14.6 
               
               
                   
               
               
                  30 
                  91 
                 UUUAAGUUAGUUAGUUGCUCUU 
                 GAGCAACUAACUAACUUAAA 
                  68.26 
                 20.91 
                 84.0 
                 23.8 
                 72.3 
                 18.0 
               
               
                   
               
               
                  58 
                 119 
                 UGAAUUAAGUUAGUUAGUUGCU 
                 CAACUAACUAACUUAAUUCA 
                  89.70 
                 10.35 
                 38.6 
                  7.9 
                 46.6 
                  9.7 
               
               
                   
               
               
                   6 
                  67 
                 UUUUAAGUGAAGUUACUUCUGG 
                 AGAAGUAACUUCACUUAAAA 
                  80.06 
                 43.88 
                 53.1 
                 14.8 
                 87.3 
                 51.1 
               
               
                   
               
               
                  11 
                  72 
                 UGUAUAACCUUCCAUUUUGAGA 
                 UCAAAAUGGAAGGUUAUACA 
                 127.61 
                 23.10 
                 34.0 
                 11.6 
                 36.4 
                 11.5 
               
               
                   
               
               
                  12 
                  73 
                 UUUUAUAGAGUAUAACCUUCCA 
                 GAAGGUUAUACUCUAUAAAA 
                  39.2 
                 18.6 
                 32.9 
                 10.2 
                 26.0 
                 10.8 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Exemplary Sequences of the Present Application and 
               
               
                 Their in vivo Potency and Duration Evaluations in Silencing Human Angplt3 
               
               
                 mRNA and Reducing Serum Protein in Humanized Transgenic Mice 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 % mRNA  
                 serum protein 
               
               
                 Guide 
                 Passenger 
                   
                   
                 remaining 
                 levels (ng/ml) 
               
               
                 Strand 
                 Strand 
                   
                   
                 on day 14 
                 on day 14 
               
               
                 SEQ 
                 SEQ 
                 Guide strand 
                 Passenger strand  
                 at 0.5 mg/kg 
                 at 0.5 mg/kg 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 ID NOs 
                 ID NOs 
                 sequence (5′-3′) 
                 sequence (5′-3′) 
                 Mean 
                 SEM 
                 Mean 
                 SEM 
               
               
                   
               
               
                 278 
                 134 
                 UUAGCAAAUCUUGAUUUUGGCU 
                 CCAAAAUCAAGAUUUGCUAA 
                  27.50 
                  2.65 
                 17.51 
                  2.47 
               
               
                   
               
               
                  19 
                  80 
                 UCAUAGCAAAUCUUGAUUUUGG 
                 AAAAUCAAGAUUUGCUAUGA 
                  30.50 
                  9.57 
                 14.35 
                  2.26 
               
               
                   
               
               
                  48 
                 109 
                 UUUUACAUCGUCUAACAUAGCA 
                 CUAUGUUAGACGAUGUAAAA 
                 101.50 
                 15.97 
                 52.53 
                  6.73 
               
               
                   
               
               
                   3 
                  64 
                 UAAAUUUUUACAUCGUCUAACA 
                 UUAGACGAUGUAAAAAUUUA 
                 139.50 
                 20.34 
                 68.65 
                  4.66 
               
               
                   
               
               
                  24 
                  85 
                 UGAUAGAUCAUAAAAAGACUGA 
                 AGUCUUUUUAUGAUCUAUCA 
                  46.50 
                  7.19 
                 26.63 
                  3.33 
               
               
                   
               
               
                  54 
                 115 
                 UUUAUAUGUAGUUCUUCUCAGU 
                 UGAGAAGAACUACAUAUAAA 
                  66.25 
                  4.19 
                 32.69 
                  7.28 
               
               
                   
               
               
                  27 
                  88 
                 UUAGUUUAUAUGUAGUUCUUCU 
                 AAGAACUACAUAUAAACUAA 
                  32.25 
                  9.39 
                 17.35 
                  2.85 
               
               
                   
               
               
                  55 
                 116 
                 UCAAGUGACAUAUUCUUUACCU 
                 GUAAAGAAUAUGUCACUUGA 
                 131.50 
                 11.96 
                 57.20 
                  9.59 
               
               
                   
               
               
                  56 
                 117 
                 UUUGAGUUGAGUUCAAGUGACA 
                 UCACUUGAACUCAACUCAAA 
                  60.75 
                 21.61 
                 36.62 
                  3.66 
               
               
                   
               
               
                  30 
                  91 
                 UUUAAGUUAGUUAGUUGCUCUU 
                 GAGCAACUAACUAACUUAAA 
                 113.30 
                 18.91 
                 49.54 
                  6.51 
               
               
                   
               
               
                  31 
                  92 
                 UAUUAAGUUAGUUAGUUGCUCU 
                 AGCAACUAACUAACUUAAUA 
                  90.25 
                 16.26 
                 51.36 
                  9.89 
               
               
                   
               
               
                  62 
                 123 
                 UUUUAUUUGACUAUGCUGUUGG 
                 AACAGCAUAGUCAAAUAAAA 
                 152.80 
                 19.40 
                 57.56 
                 10.48 
               
               
                   
               
               
                   9 
                  70 
                 UGAAAAACUUGAGAGUUGCUGG 
                 AGCAACUCUCAAGUUUUUCA 
                  75.25 
                 19.38 
                 32.54 
                  4.04 
               
               
                   
               
               
                  41 
                 102 
                 UUUGAAUUAAUGUCCAUGGACU 
                 UCCAUGGACAUUAAUUCAAA 
                  72.50 
                 11.90 
                 34.27 
                  3.25 
               
               
                   
               
               
                   4 
                  65 
                 UAUAAAAAGACUGAUCAAAUAU 
                 AUUUGAUCAGUCUUUUUAUA 
                  61.50 
                 12.23 
                 38.09 
                  4.65 
               
               
                   
               
               
                   5 
                  66 
                 UGACAUAUUCUUUACCUCUUCA 
                 AAGAGGUAAAGAAUAUGUCA 
                  69.75 
                  7.23 
                 49.87 
                 11.49 
               
               
                   
               
               
                 558 
                 447 
                 UAGAAUUUUUUCUUCUAGGAGG 
                 UCCUAGAAGAAAAAAUUCUA 
                  85.25 
                 14.84 
                 50.98 
                  8.71 
               
               
                   
               
               
                  60 
                 121 
                 UUUGUUGAAGUAGAAUUUUUUC 
                 AAAAAUUCUACUUCAACAAA 
                  89.75 
                 18.82 
                 54.25 
                 11.35 
               
               
                   
               
               
                  61 
                 122 
                 UUUCACUUUUUGUUGAAGUAGA 
                 UACUUCAACAAAAAGUGAAA 
                  94.75 
                 11.15 
                 49.20 
                  3.87 
               
               
                   
               
               
                  34 
                  95 
                 UUUAGUUAGUUGCUCUUCUAAA 
                 UAGAAGAGCAACUAACUAAA 
                  90.50 
                 13.23 
                 56.26 
                 14.83 
               
               
                   
               
               
                  10 
                  71 
                 UUAAUGUUUGUUGUCUUUCCAG 
                 GGAAAGACAACAAACAUUAA 
                  46.00 
                  8.08 
                 34.03 
                  6.33 
               
               
                   
               
            
           
         
       
     
     EXAMPLES 
     Example 1: Design and Testing of siRNA Compounds Against ANGPTL-3 mRNA 
     The example described herein determined the potency of the siRNA compounds against human Angptl3 mRNA (Table 2, Set 1 and Set 2). 
     Materials and Methods 
     In Vitro Compound Screening 
     Two sets of siRNAs compounds against human Angptl3 transcript (Accession No: NM_014495.4) were designed. The first set included 176 compounds (Table 2, Set 1) and the second set included 141 compounds (Table 2, Set 2). The compounds were diluted into the desired concentration with PBS. The compounds were transfected into the cultured Huh-7 cells with Lipofectamine RNAiMAX (Invitrogen-13778-150) reagents. Each compound was tested at two concentrations of 0.02 nM ( FIG.  1   ) and 0.1 nM ( FIG.  2   ). At 24 hours post transfection, mRNA was extracted from the transfected cells using RNeasy 96 kit (Qiagen-74182). TaqMan RT-qPCR gene expression assay was conducted to analyze the compound potency in silencing Angplt3 mRNA. 
     Ex Vivo Potency Evaluation in Primary Human Hepatocytes (PHH) and Primary Cynomolgus Monkey Hepatocytes (PCH) 
     Compounds with GalNAc conjugations were tested through free-uptake in primary human hepatocytes (PHH) or primary cynomolgus hepatocytes (PCH) (Table 3). The compounds were directly added to the cultured primary hepatocytes at 8 doses (0.0013 nM, 0.0064 nM, 0.0320 nM, 0.1600 nM, 0.8000 nM, 4.0000 nM, 20.0000 nM, 100.0000 nM). 48 hrs later, the cells were harvested for mRNA analysis through RT-qPCR. The absolute IC50 was calculated with three parameters log (inhibitor) vs. response equations, as shown in Table 3. 
     In Vivo Compound Screening in Hydrodynamic Injection (HDI) Mouse Liver 
     Selected siRNA compounds with GalNAc conjugations were dosed on day 1 through subcutaneous dosing to BALB/c female animals (6-8 weeks old). Animals then received 10 μg of pcDNA3.1-hsAngptl3 plasmids on day 4. Liver biopsies were taken on day 5 for mRNA remaining analysis through RT-qPCR. 
     In Vivo Potency and Duration Evaluation in hsAngptl3 Transgenic Mice 
     The hsAngptl3 transgenic mice is a humanized mice model that replaced the endogenous wildtype mouse Angptl3 alleles with human Angptl3 coding regions, introns, and 3′UTR. The mouse promoter regions and 5′UTR remain unchanged. Selected siRNA compounds with proprietary chemical modifications and GalNAc conjugates ( FIGS.  6 A- 6 B ) were dosed into the hsAngptl3 TG mice through subcutaneous dosing at 1 mg/kg. The liver biopsies were taken on day 14 post dosing for mRNA analysis through RT-qPCR ( FIG.  6 A ). Serum hsANGPTL3 protein levels were analyzed on day −1, 4, 7, and 14 through ELISA (R&amp;D DANL30 ELISA kit) ( FIG.  6 B ). 
     Results and Observations 
     The percentage of human Angptl3 mRNA remaining in cultured Huh-7 cells relative to mock transfection when normalized to Gapdh mRNA levels, was determined for each compound following transfection into cells at a concentration of either 0.02 nM ( FIG.  1   ) or 0.1 nM ( FIG.  2   ). The results identified several compounds that were able to reduce the level of human Angptl3 mRNA in transfected cells by 20% to 50% or more than 50% or less at a concentration of 0.02 nM as (see Table 2, Set 1 and Set 2, and  FIG.  1   ). Also, several compounds were able to reduce the level of human Angptl3 mRNA in transfected cells by between 50% to 75% or more than 75% or less at a concentration of 0.1 nM (see Table 2, Set 1 and Set 2, and  FIG.  2   ). 
     Based on the potency, sixty-two siRNA compounds were identified and selected (shown with bold in Table 2). The IC 50  values of eighteen of the selected compounds was determined, among which fifteen were shown to reduce the percentage of Angptl3 mRNA in cells by 50% at a dose of less than 20 μM (see  FIGS.  3 A- 3 R ). For determining the IC50 value of the specific compounds, the Huh-7 cells were transfected with the indicated compounds at 2.3, 7, 21, 60, 190, 560, 1670, and 5000 picomolar concentration. IC50 was calculated using the three parameter Log (inhibitor) vs. response formula. As shown in  FIGS.  3 A- 3 R , data is presented as % of human Angptl3 mRNA remaining relative to Mock transfection when normalized to Gapdh mRNA levels (Mean, +/−SEM). 
     To measure in vivo potency of compounds listed in Table 2, Set 1 and Set 2, a hydrodynamic injection (HDI) mouse model was used for selected siRNA compounds containing GalNAc conjugations. Compounds were administered to BALB/c female mice (˜6-8 weeks old) at 0.5 mg/kg through subcutaneous dosing on day 1. On day 4, post-dosing, 10 μg of pcDNA3.1-hsAngptl3 plasmids were dosed through HDI and mRNA expression was examined ( FIG.  4   ). Liver biopsies were taken on day 5 and the amount of mRNA remaining was analyzed via RT-qPCR. Data is represented as % of human Angptl3 mRNA remaining relative to PBS groups when normalized to Neomycin-resistant (NeoR) gene mRNA levels (Mean, +/−SD) ( FIG.  4    and Table 4). 
     The in vivo dose response of selected siRNA compounds (Table 2, Set 1 and Set 2) was determined, as shown in  FIG.  5   . Compounds were dosed at 0.25 mg/kg (solid squares), 0.5 mg/kg (grey circles), or 1 mg/kg (triangles) subcutaneously on day 1. 10 μg of pcDNA3.1-hsAngptl3 plasmids were dosed through hydrodynamic injection (HDI) on day 4 post-dosing. Liver biopsies were taken on day 5 and the amount of mRNA remaining was analyzed via RT-qPCR. Data is represented as % of human Angptl3 mRNA remaining relative to PBS groups when normalized to NeoR mRNA levels (Mean, +/−SD) ( FIG.  5    and Table 5). 
     The compound potency and duration evaluations of selected siRNA compounds (Table 2, Set 1 and Set 2) was evaluated using a humanized transgenic mice model that expresses human Angplt3, as shown in  FIGS.  6 A- 6 B  and Table 6. Compounds were dosed at 1 mg/kg through subcutaneous dosing on day 0. Liver hsANGPTL3 mRNA levels were determined on day 14 ( FIG.  6 A  and Table 6) and are represented as % of remaining relative to PBS group. Serum ANGPLT3 proteins concentrations were evaluated compared to PBS control ( FIG.  6 B  and Table 6) and are represented as absolute values in ng/ml. 
     Several compounds were able to reduce the level of Angplt3 mRNA in transfected cells by between 20% to 50%, or greater than 50%, at either 0.02 nM or 0.1 nM, or both concentrations. Several compounds were able to reduce the level of Angplt3 mRNA in transfected cells by between 20% to 50%, by between 50% to 75%, or greater than 75%, at 0.1 nM. 
     Additionally, this work identifies several compounds that are able to reduce the level of Angplt3 mRNA in the liver in vivo. Specifically, multiple compounds are able to Angplt3 mRNA in vivo between 20% to 50%, or greater than 50%, when administered at 0.25 mg/kg, or 0.5 mg/kg, or 1 mg/kg, or a combination of these concentrations. 
     This work also identifies siRNA compounds that are able to reduce the level of human Angplt3 mRNA by between 9% and 72% in vivo and reduce the level of serum protein between 20% to 50% or greater than 50% in transgenic humanized mice 
     In summary, the present disclosure identifies numerous siRNA compounds that reduce the level of Angptl3 mRNA in target cells in vitro and in vivo and reduce serum protein levels in vivo.