Patent Publication Number: US-2021180066-A1

Title: Compositions and Methods for Inhibiting Gene Expression of Hif2alpha

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     The present application is a divisional of U.S. patent application Ser. No. 15/954,316, filed Apr. 16, 2018 which is a divisional of U.S. patent application Ser. No. 15/166,311, filed May 27, 2016 (now U.S. Pat. No. 9,976,141), which claims benefit to U.S. Provisional Patent Application Ser. No. 62/168,244 filed on May 29, 2015, the disclosure of each of which is specifically incorporated by reference herein. 
    
    
     BACKGROUND 
     EPAS1 is a member of the HIF (hypoxia inducible factor) gene family. Also known as Hif2alpha or Hif2α, EPAS1 encodes half of a transcription factor involved in the induction of genes regulated by oxygen, and which is induced as oxygen levels fall (a condition known as hypoxia). 
     Certain variants of this gene provide protection for people living at high altitude. However, at low altitude, over-expression of wild-type (WT) EPAS1 is associated with increased hypertension and stroke, and with symptoms similar to mountain sickness. Mutations in this gene are associated with erythrocytosis familial type 4 and pulmonary hypertension. EPAS1 can cause excessive production of red blood cells, leading to inhibited reproductive abilities or even death. 
     EPAS1 has been shown to be required for expression of, or enhance the expression of, various genes involved in an assortment of diseases, including tumor progression. For example, EPAS1 may play a role in the progression of uveal melanomas, possibly by promoting the autocrine loop VEGF-pVEGFR2/KDR, and by enhancing the expression of LDHA, thus conferring a growth advantage. 
     EPAS1 has also been shown to be involved in, or upregulates expression of, other factors, including: cMyc (which favors cell proliferation, transformation, neoplasia and tumorigenesis, and which is highly expressed in most cancers); Interleukin 8 (a pro-inflammatory mediator, e.g., in gingivitis and psoriasis); SP-1 (a transcription factor involved in IL-8 regulation and a coactivator of cMyc); LDH5 (which is linked with tumor necrosis and increased tumor size); and LANA (Latency Associated Nuclear Antigen, which is associated with Kaposi&#39;s sarcoma-associated Herpesvirus). In addition, HIF (hypoxia induced factor) activity may play a role in angiogenesis required for cancer tumor growth. EPAS 1 may also be involved in several other diseases, including inflammation, chronic inflammation, neovascular diseases, rheumatoid arthritis, renal cancer, clear cell renal cell carcinoma (and metastases of this and other cancers), melanoma, uveal melanoma, chondrosarcoma, and multiple myeloma. 
     Mutations in EPAS1 gene have been correlated to early onset of neuroendocrine tumors such as paragangliomas, somatostatinomas and/or pheochromocytomas. The mutations are commonly somatic missense mutations located in the primary hydroxylation site of HIF-2a. 
     These mutations are believed to disrupt the protein hydroxylation/degradation mechanism and lead to protein stabilization and pseudohypoxic signaling. In addition, neuroendocrine tumors release erythropoietin (EPO) into circulating blood, and lead to polycythemia. 
     SUMMARY 
     Described herein are Hif2α (also termed EPAS, or Hif2alpha) gene-specific RNA interference (RNAi) trigger molecules (also termed RNAi agent, RNAi trigger, or trigger) able to selectively and efficiently decrease expression of Hif2α. Each RNAi trigger includes at least a sense strand and an antisense strand. The sense strand and the antisense strand can be partially, substantially, or fully complementary to each other. The length of the RNAi trigger sense and antisense strands described herein each can be 16 to 30 nucleotides in length. In some embodiments, the sense and antisense strands are independently 17 to 26 nucleotides in length. The sense and antisense strands can be either the same length or different lengths. The RNAi triggers described herein, upon delivery to a cell expressing the Hif2α gene, inhibit the expression of the Hif2α gene in vitro or in vivo. Examples of Hif2α RNAi trigger sense strands and antisense strands that can be used in a Hif2α RNAi trigger are provided in Tables 1-2 and 5. 
     A sense strand of an Hif2α RNAi trigger contains a nucleotide sequence having at least 90% identity over a core stretch of at least 16 consecutive nucleotides to a sequence in an Hif2α mRNA. In some embodiments, the nucleotide sequence having at least 90% identity to a sequence in the Hif2α mRNA is 16, 17, 18, 19, 20, 21, 22, or 23 nucleotides in length. An antisense strand of an Hif2α RNAi trigger contains a nucleotide sequence having at least 90% complementary over a core stretch of at least 16 consecutive nucleotides to a sequence in the Hif2α mRNA and the corresponding sense strand. In some embodiments, the nucleotide sequence having at least 90% complementarity to a sequence in the Hif2α mRNA or the corresponding sense strand is 16, 17, 18, 19, 20, 21, 22, or 23 nucleotides in length. 
     In some embodiments, one or more Hif2α RNAi triggers are delivered to target cells or tissues using any oligonucleotide delivery technology known in the art. Nucleic acid delivery methods include, but are not limited to, by encapsulation in liposomes, by iontophoresis, or by incorporation into other vehicles, such as hydrogels, cyclodextrins, biodegradable nanocapsules, and bioadhesive microspheres, proteinaceous vectors or Dynamic Polyconjugates™ (DPCs). In some embodiments, an Hif2α RNAi trigger is conjugated to a targeting group, such as a integrin-binding compound. In some embodiments, an Hif2 RNAi trigger is conjugated to a delivery polymer or vehicle. The delivery polymer can be a reversibly modified membrane active polyamine. The delivery polymer can also be an integrin-targeted reversibly modified membrane active polyamine. 
     An integrin-targeted reversibly modified membrane active polyamine comprises a membrane active polyamine conjugated to one or more integrin-binding compounds via reversible physiologically labile covalent linkages. In some embodiments, the integrin targeted reversibly modified membrane active polyamine further comprises the membrane active polyamine conjugated to one or more steric stabilizers via reversible physiologically labile covalent linkages. Integrin-binding compounds can be, but are not limited to, RGD peptides and RGD mimics. Reversible physiologically labile covalent linkages include, but are not limited to, dipeptide amidobenzyl carbamate linkages, tetrapeptide linkages, and disubstituted maleamate linkages. 
     The Hif2α RNAi triggers are optionally combined with one or more additional (i.e., second, third, etc.) therapeutics. A second therapeutic can be another Hif2α RNAi trigger (e.g., a Hif2α RNAi trigger which targets a different sequence within the Hif2α target). An additional therapeutic can also be a small molecule drug, antibody, antibody fragment, and/or vaccine. The Hif2α RNAi triggers, with or without the one or more additional therapeutics, can be combined with one or more excipients to form pharmaceutical compositions. 
     The present disclosure also encompasses methods of treating a human subject having a pathological state mediated at least in part by Hif2α expression, the methods comprising the step(s) of administering to the subject a therapeutically effective amount of an Hif2α RNAi trigger or Hif2α RNAi trigger-containing composition. The method of treating a subject with an Hif2α RNAi trigger or Hif2α RNAi trigger-containing composition can optionally be combined with one or more steps of administering one or more additional (i.e., second) therapeutics or treatments. The Hif2α RNAi trigger and additional therapeutics can be administered in a single composition or they made be administered separately. Non-limited examples of additional therapeutics include, but are not limited to, VEGFR inhibitors (such as SUTENT®, NEXAVAR®, VOTRIENT®, AVASTIN®, INLYTA®, CABOZANTINIB®), Cytokines (such as IL-2, IFN-α), mTor inhibitors (such as EVEROLIMUS®, TEMSIROLIMUS®), anti-PD1 drugs (such as OPDIVO® and KEYTRUDA®), anti-CTLA4 (such as YERVOY®), drugs targeting signal transduction pathway components in cancer cells (such as VEGF, PI-3-kinase, MEK, JAK, Akt, MYC, Met, Src-family kinases, Abl, Axl, Mer), anti-PD-L1, anti-PD-L2, anti-TIM3, anti-LAG3, anti-CD28, anti-OX40, anti-OX-40L, anti-CD39. anti-CD40, anti-CD80, anti-CD86, anti-CD137, anti-41BBL, anti-TIGIT, anti-GITR, anti-GIRTL, anti-CD155, anti-Fas, anti-FasL, anti-TRAIL/TRAIL-L, IDO-1 inhibitor, and TDO-2 inhibitor. 
     The pharmaceutical compositions can be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration can be topical (e.g., by a transdermal patch), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer, intratracheal, intranasal), epidermal, transdermal, oral or parenteral. Parenteral administration includes, but is not limited to, intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; subdermal (e.g., via an implanted device), intracranial, intraparenchymal, intrathecal, and intraventricular, administration. 
     The described Hif2α RNAi triggers and/or compositions can be used in methods for therapeutic treatment of diseases, including but not limited to: cancer, renal cancer, clear cell renal cell carcinoma, non-small cell lung cancer, astrocytoma (brain cancer), bladder cancer, breast cancer, chondrosarcoma, colorectal carcinoma, gastric carcinoma, glioblastoma, head and neck squamous cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, neuroblastoma, melanoma, multiple myeloma, ovarian cancer, rectal cancer, metastases, gingivitis, psoriasis, Kaposi&#39;s sarcoma-associated herpesvirus, preemclampsia, inflammation, chronic inflammation, neovascular diseases, and rheumatoid arthritis. Such methods comprise administration of an Hif2α RNAi trigger as described herein to a subject, e.g., a human or animal subject. 
     Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. 
     Other features and advantages of the invention will be apparent from the following detailed description, and from the claims. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIG. 1 . Chemical structures representing PEG n -FCitFP-TFP modifying agents. 
         FIG. 2 . Chemical structures representing RGD-PEG n -FCitFP-TFP modifying agents. 
         FIG. 3 . Chemical structures representing RGD-PEG n -ACit-PABC-PNP modifying agents. 
         FIG. 4 . Chemical structures representing aldehyde-PEG n -FCit-PABC-PNP modifying agents. 
         FIG. 5 . Chemical structures representing aldehyde-PEG n -ACit-PABC-PNP modifying agents. 
         FIG. 6 . Chemical structures representing SPDP-PEG n -FCit-PABC-PNP modifying agents. 
         FIG. 7 . Chemical structures representing PEG n -ACit-PABC-PNP and PEG n -FCit-PABC-PNP modifying agents. 
         FIG. 8 . Graph illustrating serum SEAP levels during treatment in mice. Fold-changed in serum SEAP levels relative to day (−1) pre-dose levels. For G1 and G2, n=4. For G3, n=3. 
         FIG. 9 . Tumor gross morphology after 3 weekly treatments in mice. G1, vehicle; G2 400 μg Hif2α-ITG-DPC; G3 280 μg Hif2α-ITG-DPC. Both kidneys from each animal are shown. Tumor was implanted into the kidney shown on the right. Tumor from treatment groups were all significantly smaller and showed some discoloration when compared to controls. 
         FIG. 10 . H&amp;E staining of tumor formalin fixed paraffin sections. Thin arrows indicate apoptotic cells. Thick arrows indicate macrophage infiltration. Panel A, G1 vehicle treated. Typical tubular type RCC morphology with rare apoptotic cells (thin arrows). Panel B, G2 400 μg Hif2α-ITG-DPC treated. Massive necrotic center with numerous apoptotic cells in surrounding areas and overall loss of tumor structure. Panel C, G3 280 μg Hif2α-ITG-DPC treated. Destruction of typical tubular tumor structures with macrophage infiltration and numerous apoptotic cells. 
     
    
    
     DETAILED DESCRIPTION 
     Described herein are RNAi triggers for inhibiting expression of the Hif2α gene (referred to herein as Hif2α RNAi triggers). Each Hif2α RNAi trigger comprises a sense strand and an antisense strand. The sense strand and the antisense strand are partially, substantially, or fully complementary to each other. In some embodiments, the length of the herein described RNAi trigger sense and antisense strands are independently 16 to 30 nucleotides in length. In some embodiments, the length of the herein described RNAi trigger sense and antisense strands are independently 17 to 26 nucleotides in length. In some embodiments, the herein described RNAi trigger sense and antisense strands are independently 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 nucleotides in length. The sense and antisense strands can be either the same length or they can be different lengths. In some embodiments, the sense strand is about 19 nucleotides in length while the antisense strand is about 21 nucleotides in length. In some embodiments, the sense strand is about 21 nucleotides in length while the antisense strand is about 23 nucleotides in length. In other embodiments, the sense and antisense strands are independently 17-21 nucleotides in length. In some embodiments, both the sense and antisense strands are each 21-26 nucleotides in length. Examples of nucleotide sequences used in forming Hif2α RNAi trigger molecules are provided in Tables 1-2 and 5. 
     RNAi triggers include, but are not limited to: short interfering RNAs (siRNAs), double-strand RNAs (dsRNA), micro RNAs (miRNAs), short hairpin RNAs (shRNA), and dicer substrates (U.S. Pat. No. 8,084,599 8,349,809 and 8,513,207). The RNAi triggers described herein, upon delivery to a cell expressing the Hif2α gene, inhibit or knockdown expression of Hif2α gene in vitro or in vivo through the biological process of RNA interference (RNAi). 
     An Hif2α RNAi trigger comprises a sense strand and an antisense strand each containing a core sequence of 16-23 nucleobases in length. An antisense strand core sequence is 100% (perfectly) complementary or at least 90% (substantially) complementary to a nucleotide sequence (sometimes referred to, e.g. as a target sequence) present in the Hif2α mRNA. A sense strand core sequence is 100% (perfectly) complementary or at least 90% (substantially) complementary to a sequence in the antisense strand and thus the sense strand core sequence is perfectly identical or at least 90% identical to a nucleotide sequence (target sequence) present in the Hif2α mRNA. A sense strand core sequence can be the same length as a corresponding antisense core sequence or it can be a different length. In some embodiments, the antisense strand core sequence is 16, 17, 18, 19, 20, 21, 22, or 23 nucleotides in length. In some embodiments, the sense strand core sequence is 16, 17, 18, 19, 20, 21, 22, or 23 nucleotides in length. 
     The Hif2α RNAi trigger sense and antisense strands typically anneal to form a duplex. Within the complementary duplex region, the sense strand core sequence is at least 90% complementary or 100% complementary to the antisense core sequence. In some embodiments, the sense strand core sequence contains a sequence of at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 nucleotides that is at least 90% or 100% complementary to a corresponding 16, 17, 18, 19, 20, or 21 nucleotide sequence of the antisense strand core sequence (i.e., the sense strand and antisense core sequences of an Hif2α RNAi trigger have a region of at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 nucleotides that is at least 90% base paired or 100% base paired.) 
     As used herein, the term “sequence” or “nucleotide sequence” refers to a succession or order of nucleobases, nucleotides, and/or nucleosides, described with a succession of letters using the standard nucleotide nomenclature and the key for modified nucleotides described herein. 
     As used herein, and unless otherwise indicated, the term “complementary,” when used to describe a first nucleotide sequence (e.g., RNAi trigger sense strand or Hif2α mRNA) in relation to a second nucleotide sequence (e.g., RNAi trigger antisense strand), refers to the ability of an oligonucleotide or polynucleotide comprising the first nucleotide sequence to hybridize (form base pair hydrogen bonds) and form a duplex or double helical structure under certain conditions with an oligonucleotide or polynucleotide comprising the second nucleotide sequence. Complementary sequences include Watson-Crick base pairs or non-Watson-Crick base pairs and include natural or modified nucleotides or nucleotide mimics as long as the above requirements with respect to their ability to hybridize are fulfilled. “Perfectly complementary” or “fully complementary” means that all (100%) of the bases in a contiguous sequence of a first polynucleotide will hybridize with the same number of bases in a contiguous sequence of a second polynucleotide. The contiguous sequence may comprise all or a part of a first or second nucleotide sequence. As used herein, “partial complementary” means that in a hybridized pair of nucleobase sequences, at least 70% of the bases in a contiguous sequence of a first polynucleotide will hybridize with the same number of bases in a contiguous sequence of a second polynucleotide. As used herein, “substantial complementary” means that in a hybridized pair of nucleobase sequences, at least 85% of the bases in a contiguous sequence of a first polynucleotide will hybridize with the same number of bases in a contiguous sequence of a second polynucleotide. The terms “complementary”, “fully complementary” and “substantially complementary” as used herein may be used with respect to the base matching between the sense strand and the antisense strand of an RNAi trigger, or between the antisense strand of an RNAi trigger and a sequence of an Hif2α mRNA. Sequence identity or complementarity is independent of modification. For the purposes of determining identity or complementarity, for example, a and Af are complementary to U (or T) and identical to A. 
     The sense strand and/or the antisense strand may optionally and independently contain an additional 1, 2, 3, 4, 5, or 6 nucleotides (extension) at the 3′ end, the 5′ end, or both the 3′ and 5′ ends of the core sequences. The antisense strand additional nucleotides, if present, may or may not be complementary to the corresponding sequence in the Hif2α mRNA. The sense strand additional nucleotides, if present, may or may not be identical to the corresponding sequence in the Hif2α mRNA. The antisense strand additional nucleotides, if present, may or may not be complementary to the corresponding sense strand&#39;s additional nucleotides, if present. 
     As used herein, an extension comprises 1, 2, 3, 4, 5, or 6 nucleotides at the 5′ and/or 3′ end of the sense strand core sequence and/or antisense strand core sequence. The extension nucleotides on a sense strand may or may not be complementary to nucleotides, either core sequence nucleotides or extension nucleotides, in the corresponding antisense strand. Conversely, the extension nucleotides on an antisense strand may or may not be complementary to nucleotides, either core sequence nucleotides or extension nucleotides, in the corresponding sense strand. In some embodiments, both the sense strand and the antisense strand of an RNAi trigger contain 3′ and 5′ extensions. In some embodiments, one or more of the 3′ extension nucleotides of one strand base pairs with one or more 5′ extension nucleotides of the other strand. In other embodiments, one or more of 3′ extension nucleotides of one strand do not base pair with one or more 5′ extension nucleotides of the other strand. In some embodiments, an Hif2α RNAi trigger has an antisense strand having a 3′ extension and a sense strand having a 5′ extension. 
     In some embodiments an Hif2α RNAi trigger molecule comprises an antisense strand having a 3′ extension of 1, 2, 3, 4, 5, or 6 nucleotides in length. In other embodiments, an Hif2α RNAi trigger molecule comprises an antisense strand having a 3′ extension of 1, 2, or 3 nucleotides in length. In some embodiments, one or more of the antisense strand extension nucleotides comprise uracil or thymidine nucleotides or nucleotides which are complementary to the corresponding Hif2α mRNA sequence. In some embodiments, the antisense strand extension can be, but is not limited to: uAu, uGu, udTsdT, usdTsdT, UfAu, Aua, Afsusa, UAU, uAfu, uau, udAu, uscu, usgu, uscsu, cAu, aUa, aua, u(invdA)u, cag, agu, gcg, caa, usasu, uAMTM, or usTMsAM (each listed 5′ to 3′, notation is the same as for Table 2). 
     In some embodiments, an Hif2α RNAi trigger molecule comprises an antisense strand having a 5′ extension of 1, 2, 3, 4, or 5 nucleotides in length. In other embodiments, an Hif2α RNAi trigger molecule comprises an antisense strand having a 5′ extension of 1 or 2 nucleotides in length. In some embodiments, one or more of the antisense strand extension nucleotides comprises uracil or thymidine nucleotides or nucleotides which are complementary to the corresponding Hif2α mRNA sequence. In some embodiments, the antisense strand extension includes or consists of dA, dT, pdT, vpdT, or u, wherein dA and dT represent deoxyadenosine and deoxythimidine nucleotides respectively. pdT represents a deoxythimidine nucleotide having a 5′ phosphate, vpdT represents a vinylphosphonate deoxythimidine nucleotide, and u represents a 2′-OMe modified uracil nucleotide. An antisense strand may have any of the 3′ extensions described above in combination with any of the 5′ antisense strand extensions described, if present. 
     In some embodiments, an Hif2α RNAi trigger molecule comprises a sense strand having a 3′ extension of 1, 2, 3, 4, or 5 nucleotides in length. In some embodiments, one or more of the sense strand extension nucleotides comprises adenosine, uracil, or thymidine nucleotides, AT dinucleotide, or nucleotides which correspond to nucleotides in the Hif2α mRNA sequence. In some embodiments, the 3′ sense strand extension includes or consists of Af, invdA, invdT, A(invdT), Af(invdT), U(invdT), Uf(invdT), AfAbuAu, dTdT, or dTsdT, wherein Af and Uf represent 2′-fluoro adenosine and uracil nucleotides respectively, invdA and invdT represent 3′-3′ linked (inverted) deoxyadenosine and deoxythimidine nucleotides respectively, Ab represents an abasic ribose, u represents a 2′-OMe modified uracil nucleotide, dT represents a deoxythimidine nucleotide, sdT represents a deoxythimidine nucleotide having a 5′ phosphorothioate, and U and A represent uracil and adenosine ribonucleotides. 
     In some embodiments, an Hif2α RNAi trigger molecule comprises a sense strand having a 5′ extension of 1, 2, 3, 4, 5, or 6 nucleotides in length. In some embodiments, one or more of the sense strand extension nucleotides comprise uracil or adenosine nucleotides or nucleotides which correspond to nucleotides in the Hif2α mRNA sequence. In some embodiments, the sense strand 5′ extension can be, but is not limited to: uAuAus, uAuAu, UAUUAGfs, UfaUfaA, uauaA, AUAUU, AfuAfuU, auauU, uaUfau, uAuA(U UNA ), uauau, udAudAu, uuAga, uuAuu, uuGAu, uuaga, uAuga, aUaGas, uauaus, uAuaas, udAuau, adTaga, auaga, u(invdA)uau, gacau, ugaau, gcgau, uauga, uugga, or auaga (each listed 5′ to 3′. notation is the same as for Table 2). A sense strand may have a 3′ extension and/or a 5′ extension. 
     Unmodified Hif2α RNAi trigger sense strand and antisense strand sequences are provided in Tables 1 and Table 5. In forming Hif2α RNAi triggers, each of the nucleotides in each of the sequences listed in Tables 1 and 5 may be a modified nucleotide. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Unmodified Hif2α RNAi trigger antisense strand 
               
               
                 and sense strand sequences. 
               
            
           
           
               
               
               
               
            
               
                 SEQ 
                   
                 SEQ 
                   
               
               
                 ID 
                 Antisense Strand 
                 ID 
                 Sense Strand 
               
               
                 NO. 
                 Sequence 5′ → 3′ 
                 NO. 
                 Sequence 5′ → 3′ 
               
               
                   
               
               
                  1 
                 AGUAAAACAAUUGUGUACUUU 
                 57 
                 AGUACACAAUUGUUUUACUT 
               
               
                   
               
               
                  2 
                 AGUAAAACAAUUGUGUACUUU 
                 44 
                 AAAGUACACAAUUGUUUUAC 
               
               
                   
                 AA 
                   
                 T 
               
               
                   
               
               
                  3 
                 AUUCAUGAAAUCGUUACGUTG 
                 52 
                 ACGUAACGAUUUCAUGAATT 
               
               
                   
               
               
                  4 
                 AUUCAUGAAAUCGUUACGUUG 
                 52 
                 ACGUAACGAUUUCAUGAATT 
               
               
                   
               
               
                  4 
                 AUUCAUGAAAUCGUUACGUUG 
                 53 
                 ACGUAACGAUUUCAUGAAU 
               
               
                   
               
               
                  4 
                 AUUCAUGAAAUCGUUACGUUG 
                 54 
                 ACGUAACGAUUUCAUGAAUT 
               
               
                   
               
               
                  4 
                 AUUCAUGAAAUCGUUACGUUG 
                 73 
                 UAUACGUAACGAUUUCAUGA 
               
               
                   
                   
                   
                 AUT 
               
               
                   
               
               
                  4 
                 AUUCAUGAAAUCGUUACGUUG 
                 74 
                 UAUACGUAACGAUUUCAUGA 
               
               
                   
                   
                   
                 AUTT 
               
               
                   
               
               
                  5 
                 AUUCAUGAAAUCGUUACGUUG 
                 47 
                 AACGUAACGAUUUCAUGAAU 
               
               
                   
                 AT 
                   
                 T 
               
               
                   
               
               
                  6 
                 AUUCAUGAAAUCGUUACGUUG 
                 77 
                 UAUCAACGUAACGAUUUCAU 
               
               
                   
                 GC 
                   
                 GAAUTT 
               
               
                   
               
               
                  7 
                 TAAAUCGUUACGUUGACAGTT 
                 67 
                 CUGUCAACGUAACGAUUUAT 
               
               
                   
               
               
                  8 
                 TAACCACAUACGUUGGAGUTT 
                 55 
                 ACUCCAACGUAUGUGGUUAT 
               
               
                   
               
               
                  9 
                 TAAGUUAAGCUCCCAUACATT 
                 81 
                 UGUAUGGGAGCUUAACUUAT 
               
               
                   
               
               
                 10 
                 TAAUCGUUACGUUGACAGGTT 
                 63 
                 CCUGUCAACGUAACGAUUAT 
               
               
                   
               
               
                 11 
                 TACGUUGACAGGUAGGGUUTT 
                 45 
                 AACCCUACCUGUCAACGUAT 
               
               
                   
               
               
                 12 
                 TAGAGGAGCUUGUGUGUUCTT 
                 68 
                 GAACACACAAGCUCCUCUAT 
               
               
                   
               
               
                 13 
                 TAGCUUGUGUGUUCGCAGGTT 
                 62 
                 CCUGCGAACACACAAGCUAT 
               
               
                   
               
               
                 14 
                 TAGGAGCUUGUGUGUUCGCTT 
                 69 
                 GCGAACACACAAGCUCCUAT 
               
               
                   
               
               
                 15 
                 TAUCGUUACGUUGACAGGUTT 
                 49 
                 ACCUGUCAACGUAACGUAAT 
               
               
                   
               
               
                 15 
                 TAUCGUUACGUUGACAGGUTT 
                 71 
                 UAUACCUGUCAACGUAACGU 
               
               
                   
                   
                   
                 AAT 
               
               
                   
               
               
                 16 
                 TCAUGAAAUCGUUACGUUGTT 
                 60 
                 CAACGUAACGAUUUCAUGAT 
               
               
                   
               
               
                 17 
                 TCGUUACGUUGACAGGUAGTT 
                 65 
                 CUACCUGUCAACGUAACGAT 
               
               
                   
               
               
                 18 
                 TCUAGCAACAAAACCUUAATT 
                 82 
                 UUAAGGUUUUGUUGCUAGAT 
               
               
                   
               
               
                 19 
                 TGAGCUUGUGUGUUCGCAGTT 
                 66 
                 CUGCGAACACACAAGCUCAT 
               
               
                   
               
               
                 19 
                 TGAGCUUGUGUGUUCGCAGTT 
                 68 
                 GAACACACAAGCUCCUCUAT 
               
               
                   
               
               
                 20 
                 TGAGGAGCUUGUGUGUUCGTT 
                 64 
                 CGAACACACAAGCUCCUCAT 
               
               
                   
               
               
                 21 
                 TGGAGCUUGUGUGUUCGCATT 
                 79 
                 UGCGAACACACAAGCUCCAT 
               
               
                   
               
               
                 22 
                 TGGUACUGGGUGGCGUAGCTT 
                 70 
                 GCUACGCCACCCAGUACCAT 
               
               
                   
               
               
                 23 
                 TGUAAAACAAUUGUGUACUTT 
                 56 
                 AGUACACAAUUGUUUUACAT 
               
               
                   
               
               
                 24 
                 TUACGUUGACAGGUAGGGUTT 
                 48 
                 ACCCUACCUGUCAAGGUAAT 
               
               
                   
               
               
                 25 
                 TUCGUUACGUUGACAGGUATT 
                 78 
                 UCACUGUCAACGUAACGAAT 
               
               
                   
               
               
                 26 
                 TUGAUAAACACUUAACCCATT 
                 80 
                 UGGGUUAAGUGUUUAUCAAT 
               
               
                   
               
               
                 27 
                 TUGUCACGAUGCGGUGGUUTT 
                 61 
                 CAGUGCAACGCCACCCAGAT 
               
               
                   
               
               
                 28 
                 TUUCAUGAAAUCGUUACGUCG 
                 76 
                 UAUAUCGACGUAACGAUUUC 
               
               
                   
                 GCUAU 
                   
                 AUGAAA 
               
               
                   
               
               
                 29 
                 TUUCAUGAAAUCGUUACGUCG 
                 76 
                 UAUAUCGACGUAACGAUUUC 
               
               
                   
                 GCUGU 
                   
                 AUGAAA 
               
               
                   
               
               
                 30 
                 TUUCAUGAAAUCGUUACGUTT 
                 50 
                 ACGUAACGAUUUCAUGAAA 
               
               
                   
               
               
                 30 
                 TUUCAUGAAAUCGUUACGUTT 
                 51 
                 ACGUAACGAUUUCAUGAAAT 
               
               
                   
               
               
                 30 
                 TUUCAUGAAAUCGUUACGUTT 
                 72 
                 UAUACGUAACGAUUUCAUGA 
               
               
                   
                   
                   
                 AAT 
               
               
                   
               
               
                 31 
                 TUUCAUGAAAUCGUUACGUUG 
                 59 
                 CAACGUAACGAUUUCAUGAA 
               
               
                   
                 GC 
                   
                 A 
               
               
                   
               
               
                 32 
                 TUUCAUGAAAUCGUUACGUUG 
                 75 
                 UAUAUCAACGUAACGAUUUC 
               
               
                   
                 GCUAU 
                   
                 AUGAAA 
               
               
                   
               
               
                 33 
                 TUUCAUGAAAUCGUUACGUUG 
                 75 
                 UAUAUCAACGUAACGAUUUC 
               
               
                   
                 GCUGU 
                   
                 AUGAAA 
               
               
                   
               
               
                 34 
                 TUUCAUGAAAUCGUUACGUUG 
                 75 
                 UAUAUCAACGUAACGAUUUC 
               
               
                   
                 GCUTT 
                   
                 AUGAAA 
               
               
                   
               
               
                 35 
                 UCAUGAAAUCGUUACGUUGTT 
                 58 
                 CAACGUAACGAUUUCAUGA 
               
               
                   
               
               
                 35 
                 UCAUGAAAUCGUUACGUUGTT 
                 58 
                 CAACGUAACGAUUUCAUGA 
               
               
                   
               
               
                 36 
                 UCUAGCAACAAAACCUUAATT 
                 82 
                 UUAAGGUUUUGUUGCUAGAT 
               
               
                   
               
               
                 37 
                 UGUAAAACAAUUGUGUACUTT 
                 56 
                 AGUACACAAUUGUUUUACAT 
               
               
                   
               
               
                 38 
                 UGUAAAACAAUUGUGUACUUU 
                 56 
                 AGUACACAAUUGUUUUACAT 
               
               
                   
               
               
                 39 
                 UGUAAAACAAUUGUGUACUUU 
                 43 
                 AAAGUACACAAUUGUUUUAC 
               
               
                   
                 AA 
                   
                 A 
               
               
                   
               
               
                 40 
                 UUUCAUGAAAUCGUUACGUTT 
                 51 
                 ACGUAACGAUUUCAUGAAAT 
               
               
                   
               
               
                 40 
                 UUUCAUGAAAUCGUUACGUTT 
                 72 
                 UAUACGUAACGAUUUCAUGA 
               
               
                   
                   
                   
                 AAT 
               
               
                   
               
               
                 41 
                 UUUCAUGAAAUCGUUACGUUG 
                 50 
                 ACGUAACGAUUUCAUGAAA 
               
               
                   
               
               
                 41 
                 UUUCAUGAAAUCGUUACGUUG 
                 51 
                 ACGUAACGAUUUCAUGAAAT 
               
               
                   
               
               
                 41 
                 UUUCAUGAAAUCGUUACGUUG 
                 72 
                 UAUACGUAACGAUUUCAUGA 
               
               
                   
                   
                   
                 AAT 
               
               
                   
               
               
                 42 
                 UUUCAUGAAAUCGUUACGUUG 
                 46 
                 AACGUAACGAUUUCAUGAAA 
               
               
                   
                 AT 
                   
                 T 
               
               
                   
               
            
           
         
       
     
     The Hif2α RNAi triggers described herein are formed by annealing an antisense strand with a sense strand. In some embodiments, an Hif2α RNAi trigger antisense strand comprises a nucleotide sequence of any of the sequences in Tables 1 and 5. In some embodiments, an Hif2α RNAi trigger antisense strand comprises the sequence of nucleotides 1-17, 2-17, 1-18, 2-18, 1-19, 2-19, 1-20, 2-20, 1-21, 2-21, 1-22, 2-22, 1-23, 2-23, 1-24, 2-24, 1-25, 2-25, 1-26, or 2-26 of any of the sequences in Tables 1 and 5. In some embodiments, an Hif2α RNAi trigger sense strand comprises the nucleotide sequence of any of the sequences in Tables 1 and 5. In some embodiments, an Hif2α RNAi trigger sense strand comprises the sequence of nucleotides 1-17, 2-17, 1-18, 2-18, 1-19, 2-19, 1-20, 2-20, 1-21, 2-21, 1-22, 2-22, 1-23, 2-23, 1-24, 2-24, 1-25, 2-25, 1-26, or 2-26 of any of the sequences in Tables 1 and 5. 
     In some embodiments, the sense and antisense strands of the RNAi triggers described herein contain the same number of nucleotides. In some embodiments the sense and antisense strands of the RNAi triggers described herein contain different numbers of nucleotides. In some embodiments, the sense strand 5′ end and the antisense strand 3′ end of an RNAi trigger form a blunt end. In some embodiments, the sense strand 3′ end and the antisense strand 5′ end of an RNAi trigger form a blunt end. In some embodiments, both ends of an RNAi trigger form a blunt end. In some embodiments, neither end of an RNAi trigger is blunt-ended. As used herein a blunt end refers to an end of a double stranded trigger molecule in which the terminal nucleotides of the two annealed strands are complementary (form a complementary base-pair). 
     In some embodiments, the sense strand 5′ end and the antisense strand 3′ end of an RNAi trigger form a frayed end. In some embodiments, the sense strand 3′ end and the antisense strand 5′ end of an RNAi trigger form a frayed end. In some embodiments, both ends of an RNAi trigger form a frayed end. In some embodiments, neither end of an RNAi trigger is a frayed end. As used herein a frayed end refers to an end of a double stranded trigger molecule in which the terminal nucleotides of the two annealed strands from a pair (i.e. do not form an overhang) but are not complementary (i.e. form a non-complementary pair). As used herein, an overhang is a stretch of one or more unpaired nucleotides at the end of one strand of a double stranded RNAi trigger molecule. The unpaired nucleotides may be on the sense strand or the antisense strand, creating either 3′ or 5′ overhangs. In some embodiments the RNAi trigger molecule contains: a blunt end and a frayed end, a blunt end and 5′ overhang end, a blunt end and a 3′ overhang end, a frayed end and a 5′ overhand end, a frayed end and a 3′ overhang end, two 5′ overhang ends, two 3′ overhang ends, a 5′ overhang end and a 3′ overhand end, two frayed ends, or two blunt ends. 
     A nucleotide base (or nucleobase) is a heterocyclic pyrimidine or purine compound which is a constituent of all nucleic acids and includes adenine (A), guanine (G), cytosine (C), thymine (T), and uracil (U). As used herein, “G”, “g”, “C”, “c”, “A”, “a”, “U”, “u”, and “T”, each generally stand for a nucleobase, nucleoside, nucleotide or nucleotide mimic that contains guanine, cytosine, adenine, uracil and thymidine as a base. Also as used herein, the term “nucleotide” can include a modified nucleotide or nucleotide mimic, abasic site, or a surrogate replacement moiety. 
     As used herein, a “modified nucleotide” is a nucleotide other than a ribonucleotide (2′-hydroxyl nucleotide). In some embodiments, an Hif2α RNAi trigger contains one or more modified nucleotides. In some embodiments, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the nucleotides are modified. Modified nucleotides include, but are not limited to, deoxynucleotides, nucleotide mimics, abasic nucleotides (represented herein as X or Ab), 2′-modified nucleotides, 3′ to 3′ linkages (inverted)nucleotides (represented herein as invdN, invN, invn, invX), non-natural base-comprising nucleotides, bridged nucleotides, peptide nucleic acids, 2′,3′-seco nucleotide mimics (unlocked nucleobase analogues, represented herein as N UNA  or NUNA), locked nucleotides (represented herein as N LNA  or NLNA), 3′-O-Methoxy (2′ internucleotide linked) nucleotides (represented herein as 3′-OMen), 2′-F-Arabino nucleotides (represented herein as NfANA or Nf ANA ), morpholino nucleotides, vinyl phosphonate deoxyribonucleotides (represented herein as vpdN), and vinyl phosphonate nucleotides. 2′-modified nucleotides (i.e. a nucleotide with a group other than a hydroxyl group at the 2′ position of the five-membered sugar ring) include, but are not limited to, 2′-O-methyl nucleotides (represented herein as a lower case letter ‘n’ in a nucleotide sequence), 2′-deoxy-2′-fluoro nucleotides (represented herein as Nf, also represented herein as 2′-fluoro nucleotide), 2′-deoxy nucleotides (represented herein as dN), 2′-methoxyethyl (2′-O-2-methoxylethyl)nucleotides (represented herein as NM or 2′-MOE), 2′-amino nucleotides, 2′-alkyl nucleotides. It is not necessary for all positions in a given compound to be uniformly modified. Conversely, more than one modification may be incorporated in a single Hif2M RNAi trigger or even in a single nucleotide thereof. The Hif2α RNAi trigger sense strands and antisense strands may be synthesized and/or modified by methods known in the art. Modification at one nucleotide is independent of modification of another nucleotide. 
     Modified nucleotides also include nucleotides having modified nucleobases. Modified nucleobases include, but are not limited to, synthetic and natural nucleobases, 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine, 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine. 
     In some embodiments 20% or fewer of the modified nucleotides are 2′-fluoro modified nucleotides. In some embodiments, an Hif2α RNAi trigger sense strand contains a 2′-F nucleotide at position 11 from the 3′ end. In some embodiments, an Hif2α RNAi trigger sense strand contains a 2′-F nucleotide at position 12 from the 3′ end. In some embodiments, an Hif2α RNAi trigger sense strand contains a 2′-F nucleotide at position 13 from the 3′ end. In some embodiments, an Hif2α RNAi trigger sense strand contains at least two 2′-F nucleotides at positions 11, 12, and 13 from the 3′ end. In some embodiments, an Hif2α RNAi trigger sense strand contains 2′-F nucleotides at positions 11 and 12, positions 11 and 13, or positions 12 and 13 from the 3′ end. In some embodiments, an Hif2α RNAi trigger sense strand contains 2′-F nucleotides at positions 11, 12, and 13 from the 3′ end. 
     In some embodiments, an Hif2α RNAi trigger antisense strand contains a 2′-F nucleotide at position 2 from the 5′ end. In some embodiments, an Hif2α RNAi trigger antisense strand contains a 2′-F nucleotide at position 14 from the 5′ end. In some embodiments, an Hif2α RNAi trigger antisense strand contains 2′-F nucleotides at positions 2 and 14 from the 5′ end. In some embodiments, an Hif2α RNAi trigger contains at least two 2′-F nucleotides at positions 11, 12, and 13 from the 3′ end of the sense strand and at positions 2 and 14 from the 5′ end of the antisense strand. 
     In some embodiments, an Hif2α RNAi trigger antisense strand contains a 2′-F nucleotide at position 4 from the 5′ end. In some embodiments, an Hif2α RNAi trigger antisense strand contains a 2′-F nucleotide at position 6 from the 5′ end. In some embodiments, an Hif2α RNAi trigger antisense strand contains a 2′-F nucleotide at position 8 from the 5′ end. In some embodiments, an Hif2α RNAi trigger antisense strand contains a 2′-F nucleotide at position 10 from the 5′ end. In some embodiments, an Hif2α RNAi trigger antisense strand contains a 2′-F nucleotide at position 12 from the 5′ end. In some embodiments, an Hif2α RNAi trigger antisense strand contains at least two 2′-F nucleotides at positions 4, 6, 8, 10, and 12 from the 5′ end. In some embodiments, an Hif2α RNAi trigger antisense strand contains 2′-F nucleotides at positions 4 and 6, positions 4 and 8, positions 4 and 10, positions 4 and 12, positions 6 and 8, positions 6 and 10, positions 6 and 12, positions 8 and 10, positions 8 and 12, or positions 10 and 12 from the 5′ end. In some embodiments, an Hif2α RNAi trigger antisense strand contains at three 2′-F nucleotides at positions 4, 6, 8, 10, and 12 from the 5′ end. In some embodiments, an Hif2α RNAi trigger antisense strand contains at least four 2′-F nucleotides at positions 4, 6, 8, 10, and 12 from the 5′ end. In some embodiments, an Hif2α RNAi trigger antisense strand contains 2′-F nucleotides at positions 4, 6, 8, and 10, positions 4, 6, 8, and 12, positions 4, 6, 10, and 12, positions 4, 8, 10, and 12 or positions 6, 8, 10, and 12 from the 5′ end. 
     In some embodiments, an Hif2α RNAi trigger antisense strand contains a 2′-F nucleotide at position 2 and/or position 14 and one, two, or three 2′-F nucleotides at positions 11, 12, and 13 from the 5′ end. In some embodiments, an Hif2α RNAi trigger contains a 2′-F nucleotide at position 2 and/or position 14 and one, two, or three 2′-F nucleotides at positions 11, 12, and 13 from the 5′ end of the antisense strand, and at least two 2′-F nucleotides at positions 11, 12, and 13 from the 3′ end of the sense strand. 
     In some embodiments, one or more nucleotides of an Hif2α RNAi trigger are linked by non-standard linkages or backbones (i.e. modified internucleoside linkages or modified backbones). In some embodiments, a modified internucleoside linkage is a non-phosphate-containing covalent internucleoside linkage. Modified internucleoside linkages or backbones include, but are not limited to, phosphorothioates, 5′-phosphorothioate group (represented herein as a lower case ‘s’ before a nucleotide, as in sN, sn, sNf, or sdN), chiral phosphorothioates, thiophosphate, phosphorodithioates, phosphotriesters, aminoalkyl-phosphotriesters, methyl and other alkyl phosphonates including 3′-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3′-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkyl-phosphonates, thionoalkylphosphotriesters, morpholino linkages, and boranophosphates having normal 3′-5′ linkages, 2′-5′ linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3′-5′ to 5′-3′ or 2′-5′ to 5′-2′. In other embodiments, a modified internucleoside linkage or backbone lacks a phosphorus atom. Modified internucleoside linkages lacking a phosphorus atom include, but are not limited to, short chain alkyl or cycloalkyl inter-sugar linkages, mixed heteroatom and alkyl or cycloalkyl inter-sugar linkages, or one or more short chain heteroatomic or heterocyclic inter-sugar linkages. In some embodiments, modified internucleoside backbones include, but are not limited to, siloxane backbones, sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones, methylene formacetyl and thioformacetyl backbones, alkene containing backbones, sulfamate backbones, methyleneimino and methylenehydrazino backbones, sulfonate and sulfonamide backbones, amide backbones; and others having mixed N, O, S, and CH 2  component parts. 
     In some embodiments, an Hif2α RNAi trigger contains one or more modified nucleotides and one or more modified internucleoside linkages. In some embodiments, a 2′-modified nucleotide is combined with modified internucleoside linkage. For example, in some embodiments, a sense strand of an Hif2α RNAi trigger can contain 1, 2, 3, 4 phosphorothioate linkages, an antisense strand of a Hif2α RNAi trigger can contain 1, 2, 3, or 4 phosphorothioate linkages, or both the sense strand and the antisense strand independently can contain 1, 2, 3, or 4 phosphorothioate linkages. 
     In some embodiments, an Hif2α RNAi trigger sense strand contains two phosphorothioate internucleoside linkages. In some embodiments, the two phosphorothioate internucleoside linkages are between the nucleotides at positions 1-3 from the 3′ end of the sense strand. In some embodiments, the two phosphorothioate internucleoside linkages are between the nucleotides at positions 1-3, 2-4, 3-5, 4-6, 4-5, or 6-8 from the 5′ end of the sense strand. In some embodiments, an Hif2α RNAi trigger antisense strand contains four phosphorothioate internucleoside linkages. In some embodiments, the four phosphorothioate internucleoside linkages are between the nucleotides at positions 1-3 from the 5′ end of the sense strand and between the nucleotides at positions 19-21, 20-22, 21-23, 22-24, 23-25, or 24-26 from the 5′ end. In some embodiments, an Hif2α RNAi trigger contains two phosphorothioate internucleoside linkages in the sense strand and four phosphorothioate internucleoside linkages in the antisense strand. 
     In some embodiments, an Hif2α RNAi trigger is prepared or provided as a salt, mixed salt, or a free-acid. 
     Examples of antisense strands containing modified nucleotides are provided in Table 2A and Table 5B. Examples of sense strands containing modified nucleotides are provided in Table 2B and Table 5B. In Tables 2A, 2B and 5B, the following notations are used to indicate modified nucleotides:
         N=2′-OH(unmodified)ribonucleotide (capital letter without or d indication)   n=2′-OMe modified nucleotide   Nf=2′-fluoro modified nucleotide   A dN=2′-deoxynucleotides   N UNA =2′,3′-seco nucleotide mimics (unlocked nucleobase analogs)   NM=2′-methoxyethyl nucleotide   (invdN)=inverted deoxyribonucleotide (3′-3′ linked nucleotide)   (invAb)=inverted abasic nucleotide   s=phosphorothioate linked nucleotide   p=phosphate   vpdN=vinyl phosphonate deoxyribonucleotide       

     
       
         
           
               
             
               
                 TABLE 2A 
               
             
            
               
                   
               
               
                 Hif2α RNAi trigger antisense strands having 
               
               
                 modified nucleotides. 
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 Un- 
               
               
                   
                   
                   
                 mod. 
               
               
                   
                   
                 SEQ  
                 SEQ 
               
               
                 Antisense 
                 Antisense Strand Sequence 
                 ID 
                 ID 
               
               
                 Strand ID 
                 (5′ → 3′) 
                 NO. 
                 NO. 
               
               
                   
               
               
                 AM00159-AS 
                 dTGfgAfgCfuUfgUfgUfgUfuCfgCfad 
                 112 
                 21 
               
               
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AM00160-AS 
                 dTGfgUfaCfuGfgGfuGfgCfgUfaGfcd 
                 113 
                 22 
               
               
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AM00161-AS 
                 dTCfgUfuAfcGfuUfgAfcAfgGfuAfgd 
                 106 
                 17 
               
               
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AM00162-AS 
                 dTAfgCfuUfgUfgUfgUfuCfgCfaGfgd 
                 103 
                 13 
               
               
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AM00163-AS 
                 dTGfaGfcUfuGfuGfuGfuUfcGfcAfgd 
                 110 
                 19 
               
               
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AM00164-AS 
                 dTAfgGfaGfcUfuGfuGfuGfuUfcGfcd 
                 104 
                 14 
               
               
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AM00165-AS 
                 dTGfaGfgAfgCfuUfgUfgUfgUfuCfgd 
                 111 
                 20 
               
               
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AM00166-AS 
                 dTAfgAfgGfaGfcUfuGfuGfuGfuUfcd 
                 102 
                 12 
               
               
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AM00167-AS 
                 dTUfgUfcAfcGfaUfgCfgGfuGfgUfud 
                 137 
                 27 
               
               
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AM00168-AS 
                 dTAfcGfuUfgAfcAfgGfuAfgGfgUfud 
                 101 
                 11 
               
               
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AM00169-AS 
                 dTUfaCfgUfuGfaCfaGfgUfaGfgGfud 
                 135 
                 24 
               
               
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AM00170-AS 
                 dTUfcGfuUfaCfgUfuGfaCfaGfgUfad 
                 136 
                 25 
               
               
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AM00171-AS 
                 dTAfuCfgUfuAfcGfuUfgAfcAfgGfud 
                 105 
                 15 
               
               
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AM00172-AS 
                 dTAfaUfcGfuUfaCfgUfuGfaCfaGfgd 
                 100 
                 10 
               
               
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AM01770-AS 
                 dTGfuAfaAfaCfaAfuUfgUfgUfaCfud 
                 114 
                 23 
               
               
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AM01772-AS 
                 dTGfuAfaAUNAaCfaAfuUfgUfgUfaCf 
                 116 
                 23 
               
               
                   
                 udTsdT 
                   
                   
               
               
                   
               
               
                 AM01773-AS 
                 dTGfuAfaAfAUNACfaAfuUfgUfgUfaC 
                 115 
                 23 
               
               
                   
                 fudTsdT 
                   
                   
               
               
                   
               
               
                 AM01775-AS 
                 dTCfuAfgCfaAfcAfaAfaCfcUfuAfad 
                 107 
                 18 
               
               
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AM01777-AS 
                 dTCfuAfgCUNAaAfcAfaAfaCfcUfuAf 
                 109 
                 18 
               
               
                   
                 adTsdT 
                   
                   
               
               
                   
               
               
                 AM01778-AS 
                 dTCfuAfgCfAUNAAfcAfaAfaCfcUfuA 
                 108 
                 18 
               
               
                   
                 fadTsdT 
                   
                   
               
               
                   
               
               
                 AM01780-AS 
                 dTAfaAfuCfgUfuAfcGfuUfgAfcAfgd 
                  94 
                  7 
               
               
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AM01782-AS 
                 dTAfaAfuCUNAgUfuAfcGfuUfgAfcAf 
                  96 
                  7 
               
               
                   
                 sgdTdT 
                   
                   
               
               
                   
               
               
                 AM01783-AS 
                 dTAfaAfuCfGUNAUfuAfcGfuUfgAfcA 
                  95 
                  7 
               
               
                   
                 fgdTsdT 
                   
                   
               
               
                   
               
               
                 AM01784-AS 
                 dTUfuCfaUfgAfaAfuCfgUfuAfcGfud 
                 138 
                 30 
               
               
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AM01786-AS 
                 dTUfuCfaUUNAgAfaAfuCfgUfuAfcGf 
                 145 
                 30 
               
               
                   
                 udTsdT 
                   
                   
               
               
                   
               
               
                 AM01787-AS 
                 dTUfuCfaUfGUNAAfaAfuCfgUfuAfcG 
                 144 
                 30 
               
               
                   
                 fudTsdT 
                   
                   
               
               
                   
               
               
                 AM01789-AS 
                 dTAfaGfuUfaAfgCfuCfcCfaUfaCfad 
                  97 
                  9 
               
               
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AM01791-AS 
                 dTAfaGfuUUNAaAfgCfuCfcCfaUfaCf 
                  99 
                  9 
               
               
                   
                 adTsdT 
                   
                   
               
               
                   
               
               
                 AM01792-AS 
                 dTAfaGfuUfAUNAAfgCfuCfcCfaUfaC 
                  98 
                  9 
               
               
                   
                 fadTsdT 
                   
                   
               
               
                   
               
               
                 AM02090-AS 
                 dTUfuCfaUfgAUNAaAfuCfgUfuAfcGf 
                 143 
                 30 
               
               
                   
                 udTsdT 
                   
                   
               
               
                   
               
               
                 AM02091-AS 
                 dTUfuCfaUfgAfAUNAAfuCfgUfuAfcG 
                 142 
                 30 
               
               
                   
                 fudTsdT 
                   
                   
               
               
                   
               
               
                 AM02092-AS 
                 dTUfuCfaUfgAfaAfuCfgUfUUNAAfcG 
                 139 
                 30 
               
               
                   
                 fudTsdT 
                   
                   
               
               
                   
               
               
                 AM02133-AS 
                 dTUfuCfaUfgAfaAfucgUfuAfcGfudT 
                 141 
                 30 
               
               
                   
                 sdT 
                   
                   
               
               
                   
               
               
                 AM02140-AS 
                 dTsUfsuCfaUfgAfaAfucgUfuAfcGfu 
                 128 
                 31 
               
               
                   
                 Ufgsgsc 
                   
                   
               
               
                   
               
               
                 AM02145-AS 
                 dTsUfsuCfaUfgAfaAfucgUfuAfcGfu 
                 127 
                 33 
               
               
                   
                 UfggscsuGu 
                   
                   
               
               
                   
               
               
                 AM02146-AS 
                 dTsUfsuCfaUfgAfaAfucgUfuAfcGfu 
                 123 
                 29 
               
               
                   
                 CfggscsuGu 
                   
                   
               
               
                   
               
               
                 AM02147-AS 
                 dTsUfsuCfaUfgAfaAfucgUfuAfcGfu 
                 126 
                 32 
               
               
                   
                 UfggscsuAu 
                   
                   
               
               
                   
               
               
                 AM02150-AS 
                 dTsUfsuCfaUfgAfaAfucgUfuAfcGfu 
                 125 
                 34 
               
               
                   
                 UfggcusdTsdT 
                   
                   
               
               
                   
               
               
                 AM02327-AS 
                 pdTUfuCfaUfgAfaAfuCfgUfuAfcGfu 
                 147 
                 30 
               
               
                   
                 dTsdT 
                   
                   
               
               
                   
               
               
                 AM02341-AS 
                 dTsUfsuCfaUfgAUNAaAfuCfgUfuAfc 
                 130 
                 28 
               
               
                   
                 GfuCfggscsuAu 
                   
                   
               
               
                   
               
               
                 AM02342-AS 
                 dTsUfuCfaUfgAUNAaAfuCfgUfuAfcG 
                 134 
                 28 
               
               
                   
                 fuCfggcsuAu 
                   
                   
               
               
                   
               
               
                 AM02345-AS 
                 dTsUfsuCfaUfgAfAUNAAfuCfgUfuAf 
                 129 
                 28 
               
               
                   
                 cGfuCfggscsuAu 
                   
                   
               
               
                   
               
               
                 AM02346-AS 
                 dTsUfuCfaUfgAfAUNAAfuCfgUfuAfc 
                 133 
                 28 
               
               
                   
                 GfuCfggcsuAu 
                   
                   
               
               
                   
               
               
                 AM02508-AS 
                 dTsUfsuCfaUfgAfaAfuCfgUfuAfcGf 
                 120 
                 30 
               
               
                   
                 udTsdT 
                   
                   
               
               
                   
               
               
                 AM02509-AS 
                 dTUfuCfaUfgAfaAfucGfUfuAfcGfud 
                 140 
                 30 
               
               
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AM02523-AS 
                 dTsAfsaCfcAfcAfuAfcGfuUfgGfaGf 
                 117 
                  8 
               
               
                   
                 udTsdT 
                   
                   
               
               
                   
               
               
                 AM02525-AS 
                 dTsUfsgAfuAfaAfcAfcUfuAfaCfcCf 
                 119 
                 26 
               
               
                   
                 adTsdT 
                   
                   
               
               
                   
               
               
                 AM02527-AS 
                 dTsCfsaUfgAfaAfuCfgUfuAfcGfuUf 
                 118 
                 16 
               
               
                   
                 gdTsdT 
                   
                   
               
               
                   
               
               
                 AM02529-AS 
                 usCfsaUfgAfaAfuCfgUfuAfcGfuUfg 
                 148 
                 35 
               
               
                   
                 dTsdT 
                   
                   
               
               
                   
               
               
                 AM02604-AS 
                 dTsUfsuCfaUfgAfaAfucGfUfuAfcGf 
                 122 
                 30 
               
               
                   
                 udTsdT 
                   
                   
               
               
                   
               
               
                 AM02605-AS 
                 dTsUfsuCfaUfgAfaAfucgUfuAfcGfu 
                 124 
                 30 
               
               
                   
                 dTsdT 
                   
                   
               
               
                   
               
               
                 AM02848-AS 
                 dTsUfuCfaUfgAfaAfucGfUfuAfcGfu 
                 132 
                 30 
               
               
                   
                 dTsdT 
                   
                   
               
               
                   
               
               
                 AM02849-AS 
                 dTsUfuCfaUfgAfaAfuCfgUfUfacGfu 
                 131 
                 30 
               
               
                   
                 dTsdT 
                   
                   
               
               
                   
               
               
                 AM02850-AS 
                 dTsUfsuCfaUfgAfaAfuCfgUfUfacGf 
                 121 
                 30 
               
               
                   
                 udTsdT 
                   
                   
               
               
                   
               
               
                 AM02998-AS 
                 usUfsuCfaUfgAfaAfucgUfuAfcGfud 
                 160 
                 40 
               
               
                   
                 TsdT 
                   
                   
               
               
                   
               
               
                 AM03000-AS 
                 usCfsuAfgCfaAfcAfaaAfCfcUfuAfa 
                 151 
                 36 
               
               
                   
                 dTsdT 
                   
                   
               
               
                   
               
               
                 AM03001-AS 
                 usCfsuAfgCfaaCfAfaaAfCfcUfuAfa 
                 149 
                 36 
               
               
                   
                 dTsdT 
                   
                   
               
               
                   
               
               
                 AM03002-AS 
                 usCfsuAfgCfaAfcAfaAfaCfCfuuAfa 
                 152 
                 36 
               
               
                   
                 dTsdT 
                   
                   
               
               
                   
               
               
                 AM03003-AS 
                 usCfsuAfgCfaaCfAfaAfaCfCfuuAfa 
                 150 
                 36 
               
               
                   
                 dTsdT 
                   
                   
               
               
                   
               
               
                 AM03008-AS 
                 usGfsuAfaAfaCfaAfuuGfUfgUfaCfu 
                 154 
                 37 
               
               
                   
                 dTsdT 
                   
                   
               
               
                   
               
               
                 AM03009-AS 
                 usGfsuAfaAfaCfaAfuUfgUfGfuaCfu 
                 153 
                 37 
               
               
                   
                 dTsdT 
                   
                   
               
               
                   
               
               
                 AM03059-AS 
                 pdTsUfsuCfaUfgAfaAfucgUfuAfcGf 
                 146 
                 30 
               
               
                   
                 udTsdT 
                   
                   
               
               
                   
               
               
                 AM03465-AS 
                 usUfsuCfaUfgAfaAfucgUfuAfcGfus 
                 161 
                 41 
               
               
                   
                 usg 
                   
                   
               
               
                   
               
               
                 AM03513-AS 
                 usUfsuCfaUfgAfaAfucguuacgususg 
                 162 
                 41 
               
               
                   
               
               
                 AM03514-AS 
                 usUfsuCfaUfgAfaaucguuacgususg 
                 165 
                 41 
               
               
                   
               
               
                 AM03517-AS 
                 asUfsuCfaUfgAfaAfucgUfuAfcGfus 
                  90 
                  4 
               
               
                   
                 usg 
                   
                   
               
               
                   
               
               
                 AM03685-AS 
                 usUfsuCfaUfgAfaAfucgUfuacgusus 
                 159 
                 41 
               
               
                   
                 g 
                   
                   
               
               
                   
               
               
                 AM03688-AS 
                 usUfsUfCfaugAfaAfucgUfuacgusus 
                 167 
                 41 
               
               
                   
                 g 
                   
                   
               
               
                   
               
               
                 AM03689-AS 
                 usUfsuCfaUfgAfaaucgUfuacgususg 
                 163 
                 41 
               
               
                   
               
               
                 AM03690-AS 
                 usUfsUfcaugAfaAfucgUfuacgususg 
                 166 
                 41 
               
               
                   
               
               
                 AM04001-AS 
                 usGfsuAfaAfaCfaAfuugUfgUfaCfus 
                 155 
                 38 
               
               
                   
                 usu 
                   
                   
               
               
                   
               
               
                 AM04004-AS 
                 asGfsuAfaAfaCfaAfuugUfgUfaCfus 
                  84 
                  1 
               
               
                   
                 usu 
                   
                   
               
               
                   
               
               
                 AM04007-AS 
                 usGfsuAfaAfaCfaAfuugUfgUfaCfuu 
                 156 
                 39 
               
               
                   
                 usasa 
                   
                   
               
               
                   
               
               
                 AM04010-AS 
                 asGfsuAfaAfaCfaAfuugUfgUfaCfuu 
                  85 
                  2 
               
               
                   
                 usasa 
                   
                   
               
               
                   
               
               
                 AM04015-AS 
                 asGfsuAfaAfaCfaAfuugUfguaCfuuu 
                  83 
                  2 
               
               
                   
                 sasa 
                   
                   
               
               
                   
               
               
                 AM04018-AS 
                 asGfsuAfaAfaCfaauugUfguacuuusa 
                  86 
                  2 
               
               
                   
                 sa 
                   
                   
               
               
                   
               
               
                 AM04040-AS 
                 vpusUfsuCfaUfgAfaAfucgUfuAfcGf 
                 168 
                 41 
               
               
                   
                 ususg 
                   
                   
               
               
                   
               
               
                 AM04101-AS 
                 asUfsuCfaUfgAfaaucgUfuacgususg 
                  91 
                  4 
               
               
                   
               
               
                 AM04102-AS 
                 usUfsuCfaUfgAfaaucgUfuacguugsa 
                 164 
                 42 
               
               
                   
                 s(invdT) 
                   
                   
               
               
                   
               
               
                 AM04103-AS 
                 asUfsuCfaUfgAfaaucgUfuacguugsa 
                  92 
                  5 
               
               
                   
                 s(invdT) 
                   
                   
               
               
                   
               
               
                 AM04104-AS 
                 usUfsucaugAfaAfucgUfuacgususg 
                 157 
                 41 
               
               
                   
               
               
                 AM04105-AS 
                 asUfsucaugAfaAfucgUfuacgususg 
                  88 
                  4 
               
               
                   
               
               
                 AM04106-AS 
                 asUfsucaugAfaAfucgUfuacgusTMsG 
                  87 
                  3 
               
               
                   
                 M 
                   
                   
               
               
                   
               
               
                 AM04244-AS 
                 usUfsuCfaUfgaAfaucgUfuacgususg 
                 158 
                 41 
               
               
                   
               
               
                 AM04452-AS 
                 asUfsuCfaUfgAfaaucgUfuAfcguugs 
                  93 
                  6 
               
               
                   
                 gsc 
                   
                   
               
               
                   
               
               
                 AM04455-AS 
                 asUfsuCfaUfgaAfaucgUfuAfcguugs 
                  89 
                  6 
               
               
                   
                 gsc 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 2B 
               
             
            
               
                   
               
               
                 Hif2α RNAi trigger sense strands having modified 
               
               
                 nucleotides. 
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 Unmod. 
               
               
                 Sense 
                   
                 SEQ 
                 SEQ 
               
               
                 Strand 
                   
                 ID 
                 ID 
               
               
                 ID 
                 SS Sequence 5′ → 3′ 
                 NO. 
                 NO. 
               
               
                   
               
               
                 AM00158-SS 
                 CfuGfuCfaAfcGfuAfaCfgAfuUfuAf(invdT) 
                 277 
                 67 
               
               
                   
               
               
                 AM00188-SS 
                 (NH2-C6)uAuUfgCfgAfaCfaCfaCfaAfgCfuCfcAf(invdT) 
                 265 
                 79 
               
               
                   
               
               
                 AM00189-SS 
                 (NH2-C6)uAuGfcUfaCfgCfcAfcCfcAfgUfaCfcAf(invdT) 
                 264 
                 70 
               
               
                   
               
               
                 AM00190-SS 
                 (NH2-C6)uAuCfuAfcCfuGfuCfaAfcGfuAfaCfgAf(invdT) 
                 263 
                 65 
               
               
                   
               
               
                 AM00191-SS 
                 (NH2-C6)uAuCfcUfgCfgAfaCfaCfaCfaAfgCfuAf(invdT) 
                 262 
                 62 
               
               
                   
               
               
                 AM00207-SS 
                 (NH2-C6)CfuGfcGfaAfcAfcAfcAfaGfcUfcAf(invdT) 
                 258 
                 66 
               
               
                   
               
               
                 AM00208-SS 
                 (NH2-C6)GfcGfaAfcAfcAfcAfaGfcUfcCfuAf(invdT) 
                 260 
                 69 
               
               
                   
               
               
                 AM00209-SS 
                 (NH2-C6)CfgAfaCfaCfaCfaAfgCfuCfcUfcAf(invdT) 
                 256 
                 64 
               
               
                   
               
               
                 AM00210-SS 
                 (NH2-C6)GfaAfcAfcAfcAfaGfcUfcCfuCfuAf(invdT) 
                 259 
                 68 
               
               
                   
               
               
                 AM00211-SS 
                 (NH2-C6)CfaGfuGfcAfaCfgCfcAfcCfcAfgAf(invdT) 
                 253 
                 61 
               
               
                   
               
               
                 AM00212-SS 
                 (NH2-C6)AfaCfcCfuAfcCfuGfuCfaAfcGfuAf(invdT) 
                 247 
                 45 
               
               
                   
               
               
                 AM00213-SS 
                 (NH2-C6)AfcCfcUfaCfcUfgUfcAfaGfgUfaAf(invdT) 
                 248 
                 48 
               
               
                   
               
               
                 AM00214-SS 
                 (NH2-C6)UfcAfcUfgUfcAfaCfgUfaAfcGfaAf(invdT) 
                 266 
                 78 
               
               
                   
               
               
                 AM00219-SS 
                 (NH2-C6)AfcCfuGfuCfaAfcGfuAfaCfgUfaAf(invdT) 
                 249 
                 49 
               
               
                   
               
               
                 AM00220-SS 
                 (NH2-C6)CfcUfgUfcAfaCfgUfaAfcGfaUfuAf(invdT) 
                 255 
                 63 
               
               
                   
               
               
                 AM00221-SS 
                 (NH2-C6)UfgCfgAfaCfaCfaCfaAfgCfuCfcAf(invdT) 
                 267 
                 79 
               
               
                   
               
               
                 AM00222-SS 
                 (NH2-C6)GfcUfaCfgCfcAfcCfcAfgUfaCfcAf(invdT) 
                 261 
                 70 
               
               
                   
               
               
                 AM00223-SS 
                 (NH2-C6)CfuAfcCfuGfuCfaAfcGfuAfaCfgAf(invdT) 
                 257 
                 65 
               
               
                   
               
               
                 AM00224-SS 
                 (NH2-C6)CfcUfgCfgAfaCfaCfaCfaAfgCfuAf(invdT) 
                 254 
                 62 
               
               
                   
               
               
                 AM00366-SS 
                 (Alk-SS-C6)CfuGfcGfaAfcAfcAfcAfaGfcUfcAf(invdT) 
                 220 
                 66 
               
               
                   
               
               
                 AM00367-SS 
                 (Alk-SS-C6)GfcGfaAfcAfcAfcAfaGfcUfcCfuAf(invdT) 
                 223 
                 69 
               
               
                   
               
               
                 AM00369-SS 
                 (Alk-SS-C6)GfaAfcAfcAfcAfaGfcUfcCfuCfuAf(invdT) 
                 222 
                 68 
               
               
                   
               
               
                 AM00530-SS 
                 (Alk-SS-C6)AfcCfcUfaCfcUfgUfcAfaGfgUfaAf(invdT) 
                 212 
                 48 
               
               
                   
               
               
                 AM00531-SS 
                 (Alk-SS-C6)UfcAfcUfgUfcAfaCfgUfaAfcGfaAf(invdT) 
                 224 
                 78 
               
               
                   
               
               
                 AM00543-SS 
                 (Alk-SS-C6)AfaCfcCfuAfcCfuGfuCfaAfcGfuAf(invdT) 
                 211 
                 45 
               
               
                   
               
               
                 AM00544-SS 
                 (Alk-SS-C6)AfcCfuGfuCfaAfcGfuAfaCfgUfaAf(invdT) 
                 213 
                 49 
               
               
                   
               
               
                 AM00545-SS 
                 (Alk-SS-C6)CfuAfcCfuGfuCfaAfcGfuAfaCfgAf(invdT) 
                 219 
                 65 
               
               
                   
               
               
                 AM01771-SS 
                 AfgUfaCfaCfaAfuUfgUfuUfuAfcAf(invdT) 
                 271 
                 56 
               
               
                   
               
               
                 AM01776-SS 
                 UfuAfaGfgUfuUfuGfuUfgCfuAfgAf(invdT) 
                 284 
                 82 
               
               
                   
               
               
                 AM01785-SS 
                 AfcGfuAfaCfgAfuUfuCfaUfgAfaAf(invdT) 
                 269 
                 51 
               
               
                   
               
               
                 AM01790-SS 
                 UfgUfaUfgGfgAfgCfuUfaAfcUfuAf(invdT) 
                 283 
                 81 
               
               
                   
               
               
                 AM01859-SS 
                 (Alk-SS-C6)AfgUfaCfaCfaAfuUfgUfuUfuAfcAf(invdT) 
                 218 
                 56 
               
               
                   
               
               
                 AM01860-SS 
                 (Alk-SS-C6)UfuAfaGfgUfuUfuGfuUfgCfuAfgAf(invdT) 
                 226 
                 82 
               
               
                   
               
               
                 AM01861-SS 
                 (Alk-SS-C6)CfuGfuCfaAfcGfuAfaCfgAfuUfuAf(invdT) 
                 221 
                 67 
               
               
                   
               
               
                 AM01862-SS 
                 (Alk-SS-C6)AfcGfuAfaCfgAfuUfuCfaUfgAfaAf(invdT) 
                 215 
                 51 
               
               
                   
               
               
                 AM01863-SS 
                 (Alk-SS-C6)UfgUfaUfgGfgAfgCfuUfaAfcUfuAf(invdT) 
                 225 
                 81 
               
               
                   
               
               
                 AM01994-SS 
                 (Alk-C6)uAuAfcCfuGfuCfaAfcGfuAfaCfgUfaAf(invdT) 
                 169 
                 71 
               
               
                   
               
               
                 AM02043-SS 
                 (Me-Alk-SS-C6)AfcGfuAfaCfgAfuUfuCfaUfgAfaAf(invdT) 
                 231 
                 51 
               
               
                   
               
               
                 AM02093-SS 
                 (DBCO-TEG)uAuAfcGfuAfaCfgAfuUfuCfaUfgAfaAf(invdT) 
                 228 
                 72 
               
               
                   
               
               
                 AM02135-SS 
                 (Alk-SS-C6)AfcGfuAfaCfGfAfuUfuCfaUfgAfaAf(invdT) 
                 216 
                 51 
               
               
                   
               
               
                 AM02137-SS 
                 (Alk-SS-C6)AfcGfuAfAfCfgAfuUfuCfaUfgAfaAf(invdT) 
                 217 
                 51 
               
               
                   
               
               
                 AM02139-SS 
                 (Alk-SS-C6)AfcGfuaaCfgAfuUfuCfaUfgAfaAf(invdT) 
                 214 
                 51 
               
               
                   
               
               
                 AM02142-SS 
                 CfsasAfcGfuAfaCfGfAfuUfuCfaUfgAfaAf(C6-SS-Alk-Me) 
                 276 
                 59 
               
               
                   
               
               
                 AM02144-SS 
                 CUNAsasAfcGfuAfaCfGfAfuUfuCfaUfgAfaAf(C6-SS-Alk-Me) 
                 278 
                 59 
               
               
                   
               
               
                 AM02149-SS 
                 uAuAusCfsaAfcGfuAfaCfGfAfuUfuCfaUfgAfaAf(C6-SS-Alk-Me) 
                 280 
                 75 
               
               
                   
               
               
                 AM02163-SS 
                 uAuAusCfsgAfcGfuAfaCfGfAfuUfuCfaUfgAfaAf(C6-SS-Alk-Me) 
                 282 
                 76 
               
               
                   
               
               
                 AM02363-SS 
                 (DBCO-TEG)uAuAusCfsgAfcGfuAfaCfgAfuUfuCfaUfgAfa(invdA) 
                 230 
                 76 
               
               
                   
               
               
                 AM02364-SS 
                 uAuAusCfsgAfcGfuAfaCfgAfuUfuCfaUfgAfaAf(C6-SS-Alk-Me) 
                 281 
                 76 
               
               
                   
               
               
                 AM02365-SS 
                 uAuAusCfgAfcGfuAfaCfgAfuUfuCfaUfgAfaAf(C6-SS-Alk-Me) 
                 279 
                 76 
               
               
                   
               
               
                 AM02456-SS 
                 (Alk-SMPT-C6)AfcGfuAfaCfgAfuUfuCfaUfgAfaAf(invdT) 
                 193 
                 51 
               
               
                   
               
               
                 AM02510-SS 
                 (Me-Alk-SS-C6)AfcGfuAfaCfGfAfuUfuCfaUfgAfaAf(invdT) 
                 232 
                 51 
               
               
                   
               
               
                 AM02512-SS 
                 (Me-Alk-SS-C6)AfcGfuAfacGfAfuUfuCfaUfgAfaAf(invdT) 
                 233 
                 51 
               
               
                   
               
               
                 AM02522-SS 
                 (NH2-C6)AfcUfcCfaAfcGfuAfuGfuGfgUfuAf(invdT) 
                 250 
                 55 
               
               
                   
               
               
                 AM02524-SS 
                 (NH2-C6)UfgGfgUfuAfaGfuGfuUfuAfuCfaAf(invdT) 
                 268 
                 80 
               
               
                   
               
               
                 AM02526-SS 
                 (NH2-C6)CfaAfcGfuAfaCfgAfuUfuCfaUfgAf(invdT) 
                 252 
                 60 
               
               
                   
               
               
                 AM02528-SS 
                 (NH2-C6)CfaAfcGfuAfaCfgAfuUfuCfaUfg(invdA) 
                 251 
                 58 
               
               
                   
               
               
                 AM02546-SS 
                 (Me-Alk-SS-C6)AfcUfcCfaAfcGfuAfuGfuGfgUfuAf(invdT) 
                 235 
                 55 
               
               
                   
               
               
                 AM02547-SS 
                 (Me-Alk-SS-C6)UfgGfgUfuAfaGfuGfuUfuAfuCfaAf(invdT) 
                 242 
                 80 
               
               
                   
               
               
                 AM02548-SS 
                 (Me-Alk-SS-C6)CfaAfcGfuAfaCfgAfuUfuCfaUfgAf(invdT) 
                 241 
                 60 
               
               
                   
               
               
                 AM02549-SS 
                 (Me-Alk-SS-C6)CfaAfcGfuAfaCfgAfuUfuCfaUfg(invdA) 
                 240 
                 58 
               
               
                   
               
               
                 AM02852-SS 
                 AfscGfuAfacGfAfuUfuCfaUfgAfaAf(C6-SS-Alk-Me) 
                 272 
                 50 
               
               
                   
               
               
                 AM02853-SS 
                 AfscGfUfaaCfgAfuUfuCfaUfgAfaAf(C6-SS-Alk-Me) 
                 273 
                 50 
               
               
                   
               
               
                 AM02856-SS 
                 (Me-Alk-SS-C6)AfcGfUfaaCfgAfuUfuCfaUfgAfaAf(invdT) 
                 234 
                 51 
               
               
                   
               
               
                 AM02999-SS 
                 (DBCO-TEG)uAuAfcGfuAfaCfGfAfuUfuCfaUfgAfaAf(invdT) 
                 229 
                 72 
               
               
                   
               
               
                 AM03004-SS 
                 (Me-Alk-SS-C6)UfuAfaGfguUfUfuGfuUfgCfuAfgAf(invdT) 
                 244 
                 82 
               
               
                   
               
               
                 AM03005-SS 
                 (Me-Alk-SS-C6)uuAfaGfguUfUfuguUfgCfuAfga(invdT) 
                 246 
                 82 
               
               
                   
               
               
                 AM03006-SS 
                 (Me-Alk-SS-C6)UfuAfAfggUfuUfuGfuUfgCfuAfgAf(invdT) 
                 243 
                 82 
               
               
                   
               
               
                 AM03007-SS 
                 (Me-Alk-SS-C6)uuAfAfggUfuUfuguUfgCfuAfga(invdT) 
                 245 
                 82 
               
               
                   
               
               
                 AM03010-SS 
                 (Me-Alk-SS-C6)AfgUfaCfacAfAfuUfgUfuUfuAfcAf(invdT) 
                 236 
                 56 
               
               
                   
               
               
                 AM03011-SS 
                 (Me-Alk-SS-C6)agUfaCfacAfAfuUfgUfuuuAfca(invdT) 
                 238 
                 56 
               
               
                   
               
               
                 AM03012-SS 
                 (Me-Alk-SS-C6)AfgUfAfcaCfaAfuUfgUfuUfuAfcAf(invdT) 
                 237 
                 56 
               
               
                   
               
               
                 AM03013-SS 
                 (Me-Alk-SS-C6)agUfAfcaCfaAfuUfgUfuuuAfca(invdT) 
                 239 
                 56 
               
               
                   
               
               
                 AM03058-SS 
                 AfcGfuAfaCfGfAfuUfuCfaUfgAfaAf(invdT) 
                 270 
                 51 
               
               
                   
               
               
                 AM03307-SS 
                 agUfAfcaCfaAfuUfgUfuuuAfca(invdT) 
                 274 
                 56 
               
               
                   
               
               
                 AM03308-SS 
                 (Alk-C6-C6)AfcGfuAfaCfGfAfuUfuCfaUfgAfaAf(invdT) 
                 170 
                 51 
               
               
                   
               
               
                 AM03467-SS 
                 (Alk-SMPT-C6)AfscGfuAfaCfGfAfuUfuCfaUfgAfaa(invdT) 
                 194 
                 51 
               
               
                   
               
               
                 AM03469-SS 
                 (Alk-SMPT-C6)ascGfuAfaCfGfAfuuuCfaUfgAfaa(invdT) 
                 201 
                 51 
               
               
                   
               
               
                 AM03471-SS 
                 (Alk-SMPT-C6)ascguAfaCfgAfuuuCfaUfgAfaa(invdT) 
                 208 
                 51 
               
               
                   
               
               
                 AM03473-SS 
                 (Alk-SMPT-C6)ascGfuaaCfgAfuuuCfaugAfaa(invdT) 
                 200 
                 51 
               
               
                   
               
               
                 AM03475-SS 
                 (Alk-SMPT-C6)ascguaaCfgAfuuuCfaugaaa(invdT) 
                 204 
                 51 
               
               
                   
               
               
                 AM03516-SS 
                 (Alk-SMPT-C6)ascguaaCfgAfuuucaugaaa(invdT) 
                 203 
                 51 
               
               
                   
               
               
                 AM03519-SS 
                 (Alk-SMPT-C6)ascGfuAfaCfGfAfuuuCfaUfgAfau(invdT) 
                 202 
                 54 
               
               
                   
               
               
                 AM03687-SS 
                 (Alk-SMPT-C6)ascguaaCfGfAfuuucaugaaa(invdT) 
                 205 
                 51 
               
               
                   
               
               
                 AM03692-SS 
                 (Alk-PEGS-C6)uAuascguaaCfGfAfuuucaugaaa(invdT) 
                 185 
                 72 
               
               
                   
               
               
                 AM03694-SS 
                 (Alk-PEGS-C6)uAuascGfuAfaCfGfAfuuuCfaUfgAfau(invdT) 
                 183 
                 73 
               
               
                   
               
               
                 AM03708-SS 
                 (Alk-PEGS-C6)uAuascGfuAfaCfGfAfuuuCfaUfgAfaa(invdT) 
                 182 
                 72 
               
               
                   
               
               
                 AM03710-SS 
                 (Alk-PEGS-C6)uAuascguaaCfGfAfuuuCfaugaaa(invdT) 
                 189 
                 72 
               
               
                   
               
               
                 AM03712-SS 
                 (Alk-PEGS-C6)uAuascguaaCfGfAfuuuCfaugaau(invdT) 
                 190 
                 73 
               
               
                   
               
               
                 AM03714-SS 
                 (Alk-PEG5-C6)(Alk-PEG5-Ser)- 
                 180 
                 72 
               
               
                   
                 uAuascguaaCfGfAfuuuCfaugaaa(invdT) 
                   
                   
               
               
                   
               
               
                 AM03774-SS 
                 (Alk-C6-SMPT-C6)ascguaaCfgAfuuuCfaugaaa(invdT) 
                 174 
                 51 
               
               
                   
               
               
                 AM03829-SS 
                 (Alk-PEGS-C6)uAuascguaaCfgAfuuuCfaugaaa(invdT) 
                 184 
                 72 
               
               
                   
               
               
                 AM03830-SS 
                 (Chol-TEG)uAuascguaaCfgAfuuuCfaugaaa(invdT) 
                 227 
                 72 
               
               
                   
               
               
                 AM03831-SS 
                 ascguaaCfgAfuuuCfaugaaa(NAG13) 
                 275 
                 50 
               
               
                   
               
               
                 AM04003-SS 
                 (Alk-SMPT-C6)asgUfaCfaCfAfAfuUfgUfuuuAfca(invdT) 
                 209 
                 56 
               
               
                   
               
               
                 AM04006-SS 
                 (Alk-SMPT-C6)asgUfaCfaCfAfAfuUfgUfuuuAfcu(invdT) 
                 210 
                 57 
               
               
                   
               
               
                 AM04009-SS 
                 (Alk-SMPT-C6)asaAfgUfaCfaCfAfAfuUfgUfuuuAfc(invdA) 
                 195 
                 43 
               
               
                   
               
               
                 AM04012-SS 
                 (Alk-SMPT-C6)asaAfgUfaCfaCfAfAfuUfgUfuuuAfc(invdT) 
                 196 
                 44 
               
               
                   
               
               
                 AM04014-SS 
                 (Alk-SMPT-C6)asaaguaCfaCfAfAfuuguuuuac(invdT) 
                 198 
                 44 
               
               
                   
               
               
                 AM04017-SS 
                 (Alk-SMPT-C6)asaagUfaCfaCfAfAfuUfgUfuuuac(invdT) 
                 199 
                 44 
               
               
                   
               
               
                 AM04020-SS 
                 (Alk-SMPT-C6)asaaguacaCfAfAfuuguuuuac(invdT) 
                 197 
                 44 
               
               
                   
               
               
                 AM04107-SS 
                 (Alk-C6-SMPT-C6)ascguaaCfGfAfuuucaugaaa(invdT) 
                 175 
                 51 
               
               
                   
               
               
                 AM04107-SS 
                 (Alk-C6-SMPT-C6)ascguaaCfGfAfuuucaugaaa(invdT) 
                 175 
                 51 
               
               
                   
               
               
                 AM04109-SS 
                 (Alk-C6-SMPT-C6)ascguaaCfGfAfuuucaugaAMTM(invdT) 
                 176 
                 52 
               
               
                   
               
               
                 AM04111-SS 
                 (Alk-C6-SMPT-C6)AMsCMguaaCfGfAfuuucaugaAMTM(invdT) 
                 171 
                 52 
               
               
                   
               
               
                 AM04113-SS 
                 (Alk-C6-SMPT-C6)ascguaaCfGfAfuuucaugaasus(invdT) 
                 178 
                 54 
               
               
                   
               
               
                 AM04115-SS 
                 (Alk-C6-SMPT-C6)ascguaaCfGfAfuuucaugaasus(invAb) 
                 177 
                 53 
               
               
                   
               
               
                 AM04117-SS 
                 (Alk-C6-SMPT-C6)ascguaaCfGfAfuuucaugaau(invdT) 
                 179 
                 54 
               
               
                   
               
               
                 AM04119-SS 
                 (Alk-C6-SMPT-C6)asacguaaCfGfAfuuucaugaau(invdT) 
                 173 
                 47 
               
               
                   
               
               
                 AM04121-SS 
                 (Alk-C6-SMPT-C6)asacguaaCfGfAfuuucaugaaa(invdT) 
                 172 
                 46 
               
               
                   
               
               
                 AM04122-SS 
                 (Alk-PEGS-C6)ascguaaCfGfAfuuucaugaaa(invdT) 
                 181 
                 51 
               
               
                   
               
               
                 AM04241-SS 
                 (Alk-SMPT-C6)ascguaaCfGfAfuuucaugaaAM(invdT) 
                 206 
                 51 
               
               
                   
               
               
                 AM04243-SS 
                 (Alk-SMPT-C6)ascguaaCfGfAfuuucaugaaAMs(invdT) 
                 207 
                 51 
               
               
                   
               
               
                 AM04246-SS 
                 (Alk-PEG5-C6)uAuascguaaCfGfAfuuucaugaaAMs(invdT) 
                 186 
                 72 
               
               
                   
               
               
                 AM04248-SS 
                 (Alk-PEG5-C6)uauascguaaCfGfAfuuucaugaaAMs(invdT) 
                 187 
                 72 
               
               
                   
               
               
                 AM04451-SS 
                 (Alk-PEG5-C6)uAuascguaaCfGfAfuuucaugaaudTs(invdT) 
                 188 
                 74 
               
               
                   
               
               
                 AM04454-SS 
                 (Alk-PEG5-C6)uAucsasacguAfaCfGfAfuuucaugAfaudTs(invdT) 
                 192 
                 77 
               
               
                   
               
               
                 AM04457-SS 
                 (Alk-PEG5-C6)uAucsaacguAfaCfGfAfuuucaugAfaudTs(invdT) 
                 191 
                 77 
               
               
                   
               
               
                 AM03710-SS 
                 (Alk-PEG5-C6)uAuascguaaCfGfAfuuuCfaugaaa(invdT) 
                 189 
                 72 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Hif2α RNAi trigger duplexes with Duplex ID numbers. 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 SEQ  
                 Unmod. 
                   
                 SEQ  
                 Unmod. 
               
               
                 Duplex  
                 Antisense 
                 ID 
                 SEQ  
                 Sense Strand 
                 ID 
                 SEQ  
               
               
                 ID 
                 Strand ID 
                 NO. 
                 ID NO. 
                 ID 
                 NO. 
                 ID NO. 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 AD00086 
                 AM00159-AS 
                 112 
                 21 
                 AM00188-SS 
                 265 
                 79 
               
               
                 AD00087 
                 AM00160-AS 
                 113 
                 22 
                 AM00189-SS 
                 264 
                 70 
               
               
                 AD00088 
                 AM00161-AS 
                 106 
                 17 
                 AM00190-SS 
                 263 
                 65 
               
               
                 AD00089 
                 AM00162-AS 
                 103 
                 13 
                 AM00191-SS 
                 262 
                 62 
               
               
                 AD00102 
                 AM00163-AS 
                 110 
                 19 
                 AM00207-SS 
                 258 
                 66 
               
               
                 AD00103 
                 AM00164-AS 
                 104 
                 14 
                 AM00208-SS 
                 260 
                 69 
               
               
                 AD00104 
                 AM00165-AS 
                 111 
                 20 
                 AM00209-SS 
                 256 
                 64 
               
               
                 AD00105 
                 AM00166-AS 
                 102 
                 12 
                 AM00210-SS 
                 259 
                 68 
               
               
                 AD00106 
                 AM00167-AS 
                 137 
                 27 
                 AM00211-SS 
                 253 
                 61 
               
               
                 AD00107 
                 AM00168-AS 
                 101 
                 11 
                 AM00212-SS 
                 247 
                 45 
               
               
                 AD00108 
                 AM00169-AS 
                 135 
                 24 
                 AM00213-SS 
                 248 
                 48 
               
               
                 AD00109 
                 AM00170-AS 
                 136 
                 25 
                 AM00214-SS 
                 266 
                 78 
               
               
                 AD00110 
                 AM00171-AS 
                 105 
                 15 
                 AM00219-SS 
                 249 
                 49 
               
               
                 AD00111 
                 AM00172-AS 
                 100 
                 10 
                 AM00220-SS 
                 255 
                 63 
               
               
                 AD00112 
                 AM00159-AS 
                 112 
                 21 
                 AM00221-SS 
                 267 
                 79 
               
               
                 AD00113 
                 AM00160-AS 
                 113 
                 22 
                 AM00222-SS 
                 261 
                 70 
               
               
                 AD00114 
                 AM00161-AS 
                 106 
                 17 
                 AM00223-SS 
                 257 
                 65 
               
               
                 AD00115 
                 AM00162-AS 
                 103 
                 13 
                 AM00224-SS 
                 254 
                 62 
               
               
                 AD00215 
                 AM00163-AS 
                 110 
                 19 
                 AM00369-SS 
                 222 
                 68 
               
               
                 AD00268 
                 AM00166-AS 
                 102 
                 12 
                 AM00369-SS 
                 222 
                 68 
               
               
                 AD00269 
                 AM00169-AS 
                 135 
                 24 
                 AM00530-SS 
                 212 
                 48 
               
               
                 AD00270 
                 AM00170-AS 
                 136 
                 25 
                 AM00531-SS 
                 224 
                 78 
               
               
                 AD00274 
                 AM00168-AS 
                 101 
                 11 
                 AM00543-SS 
                 211 
                 45 
               
               
                 AD00275 
                 AM00171-AS 
                 105 
                 15 
                 AM00544-SS 
                 213 
                 49 
               
               
                 AD00276 
                 AM00161-AS 
                 106 
                 17 
                 AM00545-SS 
                 219 
                 65 
               
               
                 AD00285 
                 AM00163-AS 
                 110 
                 19 
                 AM00366-SS 
                 220 
                 66 
               
               
                 AD00286 
                 AM00164-AS 
                 104 
                 14 
                 AM00367-SS 
                 223 
                 69 
               
               
                 AD00373 
                 AM00169-AS 
                 135 
                 24 
                 AM00659-SS 
                 212 
                 48 
               
               
                 AD00374 
                 AM00170-AS 
                 136 
                 25 
                 AM00660-SS 
                 224 
                 78 
               
               
                 AD00375 
                 AM00168-AS 
                 101 
                 11 
                 AM00679-SS 
                 211 
                 45 
               
               
                 AD00376 
                 AM00171-AS 
                 105 
                 15 
                 AM00661-SS 
                 213 
                 49 
               
               
                 AD00377 
                 AM00161-AS 
                 106 
                 17 
                 AM00662-SS 
                 219 
                 65 
               
               
                 AD00988 
                 AM01772-AS 
                 116 
                 23 
                 AM01771-SS 
                 271 
                 56 
               
               
                 AD00989 
                 AM01777-AS 
                 109 
                 18 
                 AM01776-SS 
                 284 
                 82 
               
               
                 AD00990 
                 AM01782-AS 
                 96 
                 7 
                 AM00158-SS 
                 277 
                 67 
               
               
                 AD00991 
                 AM01786-AS 
                 145 
                 30 
                 AM01785-SS 
                 269 
                 51 
               
               
                 AD00992 
                 AM01791-AS 
                 99 
                 9 
                 AM01790-SS 
                 283 
                 81 
               
               
                 AD00993 
                 AM01773-AS 
                 115 
                 23 
                 AM01771-SS 
                 271 
                 56 
               
               
                 AD00994 
                 AM01778-AS 
                 108 
                 18 
                 AM01776-SS 
                 284 
                 82 
               
               
                 AD00995 
                 AM01783-AS 
                 95 
                 7 
                 AM00158-SS 
                 277 
                 67 
               
               
                 AD00996 
                 AM01787-AS 
                 144 
                 30 
                 AM01785-SS 
                 269 
                 51 
               
               
                 AD00997 
                 AM01792-AS 
                 98 
                 9 
                 AM01790-SS 
                 283 
                 81 
               
               
                 AD01020 
                 AM01772-AS 
                 116 
                 23 
                 AM01859-SS 
                 218 
                 56 
               
               
                 AD01021 
                 AM01773-AS 
                 115 
                 23 
                 AM01859-SS 
                 218 
                 56 
               
               
                 AD01022 
                 AM01770-AS 
                 114 
                 23 
                 AM01859-SS 
                 218 
                 56 
               
               
                 AD01023 
                 AM01777-AS 
                 109 
                 18 
                 AM01860-SS 
                 226 
                 82 
               
               
                 AD01024 
                 AM01778-AS 
                 108 
                 18 
                 AM01860-SS 
                 226 
                 82 
               
               
                 AD01025 
                 AM01775-AS 
                 107 
                 18 
                 AM01860-SS 
                 226 
                 82 
               
               
                 AD01026 
                 AM01782-AS 
                 96 
                 7 
                 AM01861-SS 
                 221 
                 67 
               
               
                 AD01027 
                 AM01783-AS 
                 95 
                 7 
                 AM01861-SS 
                 221 
                 67 
               
               
                 AD01028 
                 AM01780-AS 
                 94 
                 7 
                 AM01861-SS 
                 221 
                 67 
               
               
                 AD01029 
                 AM01786-AS 
                 145 
                 30 
                 AM01862-SS 
                 215 
                 51 
               
               
                 AD01030 
                 AM01787-AS 
                 144 
                 30 
                 AM01862-SS 
                 215 
                 51 
               
               
                 AD01031 
                 AM01784-AS 
                 138 
                 30 
                 AM01862-SS 
                 215 
                 51 
               
               
                 AD01032 
                 AM01791-AS 
                 99 
                 9 
                 AM01863-SS 
                 225 
                 81 
               
               
                 AD01033 
                 AM01792-AS 
                 98 
                 9 
                 AM01863-SS 
                 225 
                 81 
               
               
                 AD01034 
                 AM01789-AS 
                 97 
                 9 
                 AM01863-SS 
                 225 
                 81 
               
               
                 AD01180 
                 AM00171-AS 
                 105 
                 15 
                 AM01994-SS 
                 169 
                 71 
               
               
                 AD01214 
                 AM01784-AS 
                 138 
                 30 
                 AM02043-SS 
                 231 
                 51 
               
               
                 AD01255 
                 AM01784-AS 
                 138 
                 30 
                 AM02093-SS 
                 228 
                 72 
               
               
                 AD01256 
                 AM02090-AS 
                 143 
                 30 
                 AM01862-SS 
                 215 
                 51 
               
               
                 AD01257 
                 AM02091-AS 
                 142 
                 30 
                 AM01862-SS 
                 215 
                 51 
               
               
                 AD01258 
                 AM02092-AS 
                 139 
                 30 
                 AM01862-SS 
                 215 
                 51 
               
               
                 AD01288 
                 AM02133-AS 
                 141 
                 30 
                 AM02135-SS 
                 216 
                 51 
               
               
                 AD01289 
                 AM01784-AS 
                 138 
                 30 
                 AM02137-SS 
                 217 
                 51 
               
               
                 AD01290 
                 AM01784-AS 
                 138 
                 30 
                 AM02139-SS 
                 214 
                 51 
               
               
                 AD01291 
                 AM02140-AS 
                 128 
                 31 
                 AM02142-SS 
                 276 
                 59 
               
               
                 AD01292 
                 AM02140-AS 
                 128 
                 31 
                 AM02144-SS 
                 278 
                 59 
               
               
                 AD01293 
                 AM02145-AS 
                 127 
                 33 
                 AM02149-SS 
                 280 
                 75 
               
               
                 AD01294 
                 AM02146-AS 
                 123 
                 29 
                 AM02163-SS 
                 282 
                 76 
               
               
                 AD01295 
                 AM02147-AS 
                 126 
                 32 
                 AM02149-SS 
                 280 
                 75 
               
               
                 AD01296 
                 AM02150-AS 
                 125 
                 34 
                 AM02149-SS 
                 280 
                 75 
               
               
                 AD01391 
                 AM01784-AS 
                 138 
                 30 
                 AM01785-SS 
                 269 
                 51 
               
               
                 AD01392 
                 AM02327-AS 
                 147 
                 30 
                 AM01785-SS 
                 269 
                 51 
               
               
                 AD01404 
                 AM02341-AS 
                 130 
                 28 
                 AM02364-SS 
                 281 
                 76 
               
               
                 AD01405 
                 AM02341-AS 
                 130 
                 28 
                 AM02365-SS 
                 279 
                 76 
               
               
                 AD01406 
                 AM02342-AS 
                 134 
                 28 
                 AM02364-SS 
                 281 
                 76 
               
               
                 AD01407 
                 AM02342-AS 
                 134 
                 28 
                 AM02365-SS 
                 279 
                 76 
               
               
                 AD01408 
                 AM02345-AS 
                 129 
                 28 
                 AM02364-SS 
                 281 
                 76 
               
               
                 AD01409 
                 AM02345-AS 
                 129 
                 28 
                 AM02365-SS 
                 279 
                 76 
               
               
                 AD01410 
                 AM02346-AS 
                 133 
                 28 
                 AM02364-SS 
                 281 
                 76 
               
               
                 AD01411 
                 AM02346-AS 
                 133 
                 28 
                 AM02365-SS 
                 279 
                 76 
               
               
                 AD01424 
                 AM02345-AS 
                 129 
                 28 
                 AM02363-SS 
                 230 
                 76 
               
               
                 AD01476 
                 AM01784-AS 
                 138 
                 30 
                 AM02456-SS 
                 193 
                 51 
               
               
                 AD01522 
                 AM02133-AS 
                 141 
                 30 
                 AM02510-SS 
                 232 
                 51 
               
               
                 AD01523 
                 AM02509-AS 
                 140 
                 30 
                 AM02512-SS 
                 233 
                 51 
               
               
                 AD01524 
                 AM02508-AS 
                 120 
                 30 
                 AM02043-SS 
                 231 
                 51 
               
               
                 AD01525 
                 AM02523-AS 
                 117 
                 8 
                 AM02522-SS 
                 250 
                 55 
               
               
                 AD01526 
                 AM02525-AS 
                 119 
                 26 
                 AM02524-SS 
                 268 
                 80 
               
               
                 AD01527 
                 AM02527-AS 
                 118 
                 16 
                 AM02526-SS 
                 252 
                 60 
               
               
                 AD01528 
                 AM02529-AS 
                 148 
                 35 
                 AM02528-SS 
                 251 
                 58 
               
               
                 AD01546 
                 AM02523-AS 
                 117 
                 8 
                 AM02546-SS 
                 235 
                 55 
               
               
                 AD01547 
                 AM02525-AS 
                 119 
                 26 
                 AM02547-SS 
                 242 
                 80 
               
               
                 AD01548 
                 AM02527-AS 
                 118 
                 16 
                 AM02548-SS 
                 241 
                 60 
               
               
                 AD01549 
                 AM02529-AS 
                 148 
                 35 
                 AM02549-SS 
                 240 
                 58 
               
               
                 AD01554 
                 AM02604-AS 
                 122 
                 30 
                 AM02512-SS 
                 233 
                 51 
               
               
                 AD01555 
                 AM02605-AS 
                 124 
                 30 
                 AM02510-SS 
                 232 
                 51 
               
               
                 AD01654 
                 AM02848-AS 
                 132 
                 30 
                 AM02852-SS 
                 272 
                 50 
               
               
                 AD01655 
                 AM02848-AS 
                 132 
                 30 
                 AM02512-SS 
                 233 
                 51 
               
               
                 AD01656 
                 AM02849-AS 
                 131 
                 30 
                 AM02853-SS 
                 273 
                 50 
               
               
                 AD01657 
                 AM02849-AS 
                 131 
                 30 
                 AM02856-SS 
                 234 
                 51 
               
               
                 AD01658 
                 AM02850-AS 
                 121 
                 30 
                 AM02853-SS 
                 273 
                 50 
               
               
                 AD01659 
                 AM02850-AS 
                 121 
                 30 
                 AM02856-SS 
                 234 
                 51 
               
               
                 AD01884 
                 AM02998-AS 
                 160 
                 40 
                 AM02510-SS 
                 232 
                 51 
               
               
                 AD01885 
                 AM02998-AS 
                 160 
                 40 
                 AM02999-SS 
                 229 
                 72 
               
               
                 AD01886 
                 AM03000-AS 
                 151 
                 36 
                 AM03004-SS 
                 244 
                 82 
               
               
                 AD01887 
                 AM03001-AS 
                 149 
                 36 
                 AM03005-SS 
                 246 
                 82 
               
               
                 AD01888 
                 AM03002-AS 
                 152 
                 36 
                 AM03006-SS 
                 243 
                 82 
               
               
                 AD01889 
                 AM03003-AS 
                 150 
                 36 
                 AM03007-SS 
                 245 
                 82 
               
               
                 AD01890 
                 AM03008-AS 
                 154 
                 37 
                 AM03010-SS 
                 236 
                 56 
               
               
                 AD01891 
                 AM03008-AS 
                 154 
                 37 
                 AM03011-SS 
                 238 
                 56 
               
               
                 AD01892 
                 AM03009-AS 
                 153 
                 37 
                 AM03012-SS 
                 237 
                 56 
               
               
                 AD01893 
                 AM03009-AS 
                 153 
                 37 
                 AM03013-SS 
                 239 
                 56 
               
               
                 AD01910 
                 AM02605-AS 
                 124 
                 30 
                 AM03058-SS 
                 270 
                 51 
               
               
                 AD01911 
                 AM03059-AS 
                 146 
                 30 
                 AM03058-SS 
                 270 
                 51 
               
               
                 AD02073 
                 AM03009-AS 
                 153 
                 37 
                 AM03307-SS 
                 274 
                 56 
               
               
                 AD02074 
                 AM02605-AS 
                 124 
                 30 
                 AM03308-SS 
                 170 
                 51 
               
               
                 AD02691 
                 AM03465-AS 
                 161 
                 41 
                 AM03467-SS 
                 194 
                 51 
               
               
                 AD02692 
                 AM03465-AS 
                 161 
                 41 
                 AM03469-SS 
                 201 
                 51 
               
               
                 AD02693 
                 AM03465-AS 
                 161 
                 41 
                 AM03471-SS 
                 208 
                 51 
               
               
                 AD02694 
                 AM03465-AS 
                 161 
                 41 
                 AM03473-SS 
                 200 
                 51 
               
               
                 AD02695 
                 AM03465-AS 
                 161 
                 41 
                 AM03475-SS 
                 204 
                 51 
               
               
                 AD02733 
                 AM03513-AS 
                 162 
                 41 
                 AM03516-SS 
                 203 
                 51 
               
               
                 AD02734 
                 AM03514-AS 
                 165 
                 41 
                 AM03516-SS 
                 203 
                 51 
               
               
                 AD02735 
                 AM03517-AS 
                 90 
                 4 
                 AM03519-SS 
                 202 
                 54 
               
               
                 AD02857 
                 AM03685-AS 
                 159 
                 41 
                 AM03687-SS 
                 205 
                 51 
               
               
                 AD02858 
                 AM03688-AS 
                 167 
                 41 
                 AM03687-SS 
                 205 
                 51 
               
               
                 AD02859 
                 AM03689-AS 
                 163 
                 41 
                 AM03687-SS 
                 205 
                 51 
               
               
                 AD02860 
                 AM03690-AS 
                 166 
                 41 
                 AM03687-SS 
                 205 
                 51 
               
               
                 AD02861 
                 AM03685-AS 
                 159 
                 41 
                 AM03692-SS 
                 185 
                 72 
               
               
                 AD02862 
                 AM03517-AS 
                 90 
                 4 
                 AM03694-SS 
                 183 
                 73 
               
               
                 AD02873 
                 AM03465-AS 
                 161 
                 41 
                 AM03708-SS 
                 182 
                 72 
               
               
                 AD02874 
                 AM03465-AS 
                 161 
                 41 
                 AM03710-SS 
                 189 
                 72 
               
               
                 AD02875 
                 AM03517-AS 
                 90 
                 4 
                 AM03712-SS 
                 190 
                 73 
               
               
                 AD02876 
                 AM03465-AS 
                 161 
                 41 
                 AM03714-SS 
                 180 
                 72 
               
               
                 AD02949 
                 AM03465-AS 
                 161 
                 41 
                 AM03774-SS 
                 174 
                 51 
               
               
                 AD03011 
                 AM03465-AS 
                 161 
                 41 
                 AM03829-SS 
                 184 
                 72 
               
               
                 AD03012 
                 AM03465-AS 
                 161 
                 41 
                 AM03830-SS 
                 227 
                 72 
               
               
                 AD03013 
                 AM03465-AS 
                 161 
                 41 
                 AM03831-SS 
                 275 
                 50 
               
               
                 AD03187 
                 AM04001-AS 
                 155 
                 38 
                 AM04003-SS 
                 209 
                 56 
               
               
                 AD03188 
                 AM04004-AS 
                 84 
                 1 
                 AM04006-SS 
                 210 
                 57 
               
               
                 AD03189 
                 AM04007-AS 
                 156 
                 39 
                 AM04009-SS 
                 195 
                 43 
               
               
                 AD03190 
                 AM04010-AS 
                 85 
                 2 
                 AM04012-SS 
                 196 
                 44 
               
               
                 AD03191 
                 AM04010-AS 
                 85 
                 2 
                 AM04014-SS 
                 198 
                 44 
               
               
                 AD03192 
                 AM04015-AS 
                 83 
                 2 
                 AM04017-SS 
                 199 
                 44 
               
               
                 AD03193 
                 AM04018-AS 
                 86 
                 2 
                 AM04020-SS 
                 197 
                 44 
               
               
                 AD03215 
                 AM04040-AS 
                 168 
                 41 
                 AM03469-SS 
                 201 
                 51 
               
               
                 AD03216 
                 AM04040-AS 
                 168 
                 41 
                 AM03475-SS 
                 204 
                 51 
               
               
                 AD03253 
                 AM03689-AS 
                 163 
                 41 
                 AM04107-SS 
                 175 
                 51 
               
               
                 AD03254 
                 AM04101-AS 
                 91 
                 4 
                 AM04117-SS 
                 179 
                 54 
               
               
                 AD03255 
                 AM04102-AS 
                 164 
                 42 
                 AM04121-SS 
                 172 
                 46 
               
               
                 AD03256 
                 AM04103-AS 
                 92 
                 5 
                 AM04119-SS 
                 173 
                 47 
               
               
                 AD03257 
                 AM04104-AS 
                 157 
                 41 
                 AM04107-SS 
                 175 
                 51 
               
               
                 AD03258 
                 AM04105-AS 
                 88 
                 4 
                 AM04117-SS 
                 179 
                 54 
               
               
                 AD03259 
                 AM04106-AS 
                 87 
                 3 
                 AM04109-SS 
                 176 
                 52 
               
               
                 AD03260 
                 AM04105-AS 
                 88 
                 4 
                 AM04109-SS 
                 176 
                 52 
               
               
                 AD03261 
                 AM04105-AS 
                 88 
                 4 
                 AM04111-SS 
                 171 
                 52 
               
               
                 AD03262 
                 AM04105-AS 
                 88 
                 4 
                 AM04113-SS 
                 178 
                 54 
               
               
                 AD03263 
                 AM04105-AS 
                 88 
                 4 
                 AM04115-SS 
                 177 
                 53 
               
               
                 AD03264 
                 AM03690-AS 
                 166 
                 41 
                 AM04107-SS 
                 175 
                 51 
               
               
                 AD03265 
                 AM03689-AS 
                 163 
                 41 
                 AM03692-SS 
                 185 
                 72 
               
               
                 AD03266 
                 AM03689-AS 
                 163 
                 41 
                 AM04122-SS 
                 181 
                 51 
               
               
                 AD03345 
                 AM03689-AS 
                 163 
                 41 
                 AM04241-SS 
                 206 
                 51 
               
               
                 AD03346 
                 AM03689-AS 
                 163 
                 41 
                 AM04243-SS 
                 207 
                 51 
               
               
                 AD03347 
                 AM04244-AS 
                 158 
                 41 
                 AM04243-SS 
                 207 
                 51 
               
               
                 AD03348 
                 AM03689-AS 
                 163 
                 41 
                 AM04246-SS 
                 186 
                 72 
               
               
                 AD03349 
                 AM03689-AS 
                 163 
                 41 
                 AM04248-SS 
                 187 
                 72 
               
               
                 AD03505 
                 AM04101-AS 
                 91 
                 4 
                 AM04451-SS 
                 188 
                 74 
               
               
                 AD03506 
                 AM04452-AS 
                 93 
                 6 
                 AM04454-SS 
                 192 
                 77 
               
               
                 AD03507 
                 AM04455-AS 
                 89 
                 6 
                 AM04454-SS 
                 192 
                 77 
               
               
                 AD03508 
                 AM04452-AS 
                 93 
                 6 
                 AM04457-SS 
                 191 
                 77 
               
               
                   
               
            
           
         
       
     
     A sense strand containing a sequence listed in Table 2B can be hybridized to any antisense strand containing a sequence listed in Table 2A provided the two sequences have a region of at least 90% complementarity over a contiguous 16, 17, 18, 19, 20, or 21 nucleotide sequence. Representative Hif2α RNA triggers are represented by the Duplex ID Nos. shown in Table 3. In some embodiments an Hif2α RNAi trigger consists of any of the Duplex ID Nos. presented herein. In some embodiments an Hif2α RNAi trigger comprises of any of the Duplex ID Nos. presented herein. In some embodiments, an Hif2α RNAi trigger comprises the sense strand and antisense strand nucleotide sequences of any of the Duplex ID Nos. presented herein. In some embodiments, an Hif2α RNAi trigger comprises the sense strand and antisense strand nucleotide sequences of any of the Duplex ID Nos. presented herein and a targeting group and/or linking group wherein the targeting group and/or linking group is covalently linked to the sense strand or the antisense strand. In some embodiments, an Hif2α RNAi trigger comprises the sense strand and antisense strand modified nucleotide sequences of any of the Duplex ID Nos. presented herein. In some embodiments, an Hif2α RNAi trigger comprises the sense strand and antisense strand modified nucleotide sequences of any of the Duplex ID Nos. presented herein and a targeting group and/or linking group wherein the targeting group and/or linking group is covalently linked to the sense strand or the antisense strand. 
     In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising a nucleotide base sequence of nucleotides 2-21 of SEQ ID NO. 4. In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising a nucleotide base sequence of nucleotides 2-21 of SEQ ID NO. 4 and a sense strand comprising a nucleotide base sequence of SEQ ID NO. 53. 
     In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising a nucleotide base sequence of SEQ ID NO. 88, SEQ ID NO. 157, SEQ ID NO. 159, or SEQ ID NO. 163. In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising a nucleotide base sequence of SEQ ID NO. 88 and a sense strand comprising a nucleotide base sequence of SEQ ID NO. 179. In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising a nucleotide base sequence of SEQ ID NO. 88 and a sense strand comprising a nucleotide base sequence of SEQ ID NO. 177. In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising a nucleotide base sequence of SEQ ID NO. 157 and a sense strand comprising a nucleotide base sequence of SEQ ID NO. 175. In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising a nucleotide base sequence of SEQ ID NO. 159 and a sense strand comprising a nucleotide base sequence of SEQ ID NO. 185. In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising a nucleotide base sequence of SEQ ID NO. 163 and a sense strand comprising a nucleotide base sequence of SEQ ID NO. 185. 
     In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising SEQ ID NO. 88, SEQ ID NO. 157, SEQ ID NO. 159, or SEQ ID NO. 163. In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising SEQ ID NO. 88 and a sense strand comprising SEQ ID NO. 179. In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising SEQ ID NO. 88 and a sense strand comprising SEQ ID NO. 177. In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising SEQ ID NO. 157 and a sense strand comprising SEQ ID NO. 175. In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising SEQ ID NO. 159 and a sense strand comprising SEQ ID NO. 185. In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising SEQ ID NO. 163 and a sense strand comprising SEQ ID NO. 185. 
     In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising a nucleotide base sequence of nucleotides 2-21 of SEQ ID NO. 38. In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising a nucleotide base sequence of nucleotides 2-21 of SEQ ID NO. 38 and a sense strand comprising a nucleotide base sequence of nucleotides 1-19 of SEQ ID NO. 56. 
     In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising a nucleotide base sequence of SEQ ID NO. 86, SEQ ID NO. 155, SEQ ID NO. 156. In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising a nucleotide base sequence of SEQ ID NO. 156 and a sense strand comprising a nucleotide base sequence of SEQ ID NO. 195. In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising a nucleotide base sequence of SEQ ID NO. 86 and a sense strand comprising a nucleotide base sequence of SEQ ID NO. 197. In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising a nucleotide base sequence of SEQ ID NO. 155 and a sense strand comprising a nucleotide base sequence of SEQ ID NO. 209. 
     In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising SEQ ID NO. 86, SEQ ID NO. 155, SEQ ID NO. 156. In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising SEQ ID NO. 156 and a sense strand comprising SEQ ID NO. 195. In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising SEQ ID NO. 86 and a sense strand comprising SEQ ID NO. 197. In some embodiments, a Hif2α RNAi trigger comprises an antisense strand comprising SEQ ID NO. 155 and a sense strand comprising SEQ ID NO. 209. 
     In some embodiments, an Hif2α RNAi trigger contains or is conjugated to a targeting group, linking group, delivery polymer, delivery vehicle, and/or other non-nucleotide group. The targeting group, linking group, delivery polymer, delivery vehicle, and/or other non-nucleotide group can be covalently linked to the 3′ and/or 5′ end of either the sense strand and/or the antisense strand. In some embodiments, an Hif2α RNAi trigger can contains a targeting group, linking group, delivery polymer, delivery vehicle, or other non-nucleotide group linked to the 3′ and/or 5′ end of the sense strand. In some embodiments a targeting group, linking group, delivery polymer, delivery vehicle, or other non-nucleotide group is linked to the 5′ end of an Hif2α RNAi trigger sense strand. In some embodiments, the targeting group, linking group, delivery polymer, delivery vehicle, and/or other non-nucleotide group is linked directly or indirectly to the trigger via a linker/linking group. In some embodiments, targeting group, linking group, delivery polymer, delivery vehicle, and/or other non-nucleotide group is linked to the trigger via a labile, cleavable, or reversible bond or linker. 
     A targeting group can enhance the pharmacokinetic or biodistribution properties of an RNAi trigger or conjugate to which it is attached to improve cell- or tissue-specific distribution and cell-specific uptake of the conjugate. In some instances, binding of a targeting group to a cell or cell receptor may initiate endocytosis. A targeting group can be monovalent, divalent, trivalent, tetravalent, or have higher valency. Representative targeting groups include, without limitation, compounds with affinity to cell surface molecule, cell receptor ligands, hapten, antibodies, monoclonal antibodies, antibody fragments, and antibody mimics with affinity to cell surface molecules. 
     The RNAi trigger molecules described herein may be synthesized having a reactive group, such as an amine group, at the 5′-terminus. The reactive group may be used to subsequently attach a targeting moiety using methods typical in the art. 
     In some embodiments, an Hif2α RNAi trigger includes a linking group conjugated to the trigger. The linking group facilitates covalent linkage of the trigger to a targeting group or delivery polymer or delivery vehicle. The linking group can be linked to the 3′ or the 5′ end of the RNAi trigger sense strand or antisense strand. In some embodiments, the linking group is linked to the RNAi trigger sense strand. In some embodiments, the linking group is conjugated to the 5′ or 3′ end of an RNAi trigger sense strand. In some embodiments a linking group is conjugated to the 5′ end of an RNAi trigger sense strand. Examples of linking groups, include, but are not limited to: Alk-SMPT-C6, Alk-SS-C6, DBCO-TEG, Me-Alk-SS-C6, and C6-SS-Alk-Me, reactive groups such a primary amines and alkynes, alkyl groups, abasic ribose, ribitol, and/or PEG groups. 
     A linker or linking group is a connection between two atoms that links one chemical group (such as an RNAi trigger) or segment of interest to another chemical group (such as a targeting group or delivery polymer) or segment of interest via one or more covalent bonds. A labile linkage contains a labile bond. A linkage may optionally include a spacer that increases the distance between the two joined atoms. A spacer may further add flexibility and/or length to the linkage. Spacers may include, but are not be limited to, alkyl groups, alkenyl groups, alkynyl groups, aryl groups, aralkyl groups, aralkenyl groups, and aralkynyl groups; each of which can contain one or more heteroatoms, heterocycles, amino acids, nucleotides, and saccharides. Spacer groups are well known in the art and the preceding list is not meant to limit the scope of the description. 
     Targeting groups and linking groups include, but are not limited to, (Alk-C6), (Alk-C6-C6), (Alk-C6-SMPT-C6), (Alk-PEG5-C6), (Alk-PEG5-C6)(Alk-PEG5-Ser), (Alk-SMPT-C6), (Alk-SS-C6), (C6-SS-Alk-Me), (Chol-TEG), (DBCO-TEG), (Me-Alk-SS-C6), (NAG13), (NH2-C6). In some embodiments, any of the Hif2α RNAi trigger sense strands listed in Table 2B which contains a 3′ or 5′ targeting group or linking group, may alternatively contain no 3′ or 5′ targeting group or linking group, or may contain a different 3′ or 5′ targeting group or linking group including, but not limited to, those depicted in Table 4. 
     In some of the targeting group and linking group structures shown in Table 4, the RNAi trigger is shown and denoted by Trigger, RNA, R, or R1 or R2 (i.e. Trigger, RNA or R1 or R2 each comprises the RNAi trigger). For example, with respect to (Alk-C6-Ser), (Alk-PEG5-Ser), and (Alk-PEG13-Ser), one of R1 and R2 comprises the RNAi trigger and the other can be a hydrogen. 
     
       
         
           
               
             
               
                 TABLE 4 
               
               
                   
               
               
                 Structures representing targeting groups and linking groups. 
               
               
                   
               
             
            
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     In some embodiments, a delivery vehicle may be used to deliver an RNAi trigger to a cell or tissue. A delivery vehicle is a compound that improves delivery of the RNAi trigger to a cell or tissue. A delivery vehicle can include, or consist of, but is not limited to: a polymer, such as an amphipathic polymer, a membrane active polymer, a peptide, a melittin peptide, a melittin-like peptide, a lipid, a reversibly modified polymer or peptide, or a reversibly modified membrane active polyamine. 
     In some embodiments, the RNAi triggers can be combined with lipids, nanoparticles, polymers, liposomes, micelles, DPCs or other delivery systems available in the art. The RNAi triggers can also be chemically conjugated to targeting groups, lipids (including, but not limited to cholesterol and cholesteryl derivatives), nanoparticles, polymers, liposomes, micelles, DPCs (see, for example WO 2000/053722, WO 2008/0022309, WO 2011/104169, and WO 2012/083185, WO 2013/032829, WO 2013/158141, each of which is incorporated herein by reference), or other delivery systems available in the art. 
     In some embodiments, pharmaceutical compositions for delivering an Hif2α RNAi trigger to a tumor cell in vivo are described. Such pharmaceutical compositions can include, but are not limited to, an Hif2α RNAi trigger conjugated to delivery polymer to form an RNAi trigger-delivery polymer conjugate. In some embodiments, the delivery polymer is a membrane active polyamine. In some embodiments, the delivery polymer is a reversibly modified membrane active polyamine. 
     Hif2α RNAi Trigger-Delivery Polymer Conjugates 
     In some embodiments, we describe compositions represented by the formula: 
     
       
         
         
             
             
         
       
     
     wherein RNAi trigger is an Hif2α RNAi trigger as described herein, P is a membrane active polyamine, M 1  comprises a targeting group linked to P via reversible physiologically labile linkage L 1 , and M 2  comprises a steric stabilizer linked to P via reversible physiologically labile linkage L 2 , x is greater than 1, y is greater than or equal to 0. (M 2 -L 2 ) y -P-(L 1 -M 1 ) x , is not membrane active. As used herein, (M 2 -L 2 ) y -P-(L 1 -M 1 ) x  refers to a delivery polymer. Cleavage of (L 1 -M 1 ) and (M 2 -L 2 ) restores P to a membrane active state. In some embodiments, the value of x+y is greater than 80%, greater than 90%, or greater than 95% of the number of primary amines of P. In some embodiments, the value of x+y is greater than 80%, greater than 90%, or greater than 95% of the number of primary amines on a population of P. The value of n can be from 0.25 to 5 (one (1) RNAi trigger per every 4 polymers to 5 RNAi triggers per polymer). In some embodiments, the value of n is 0.5 to 5. In some embodiments, n is 0.5-2. In some embodiments, n is 0.8-1.6. In some embodiments, x is 1-20, 2-20, 3-20, 4-20, 5-20, 6-20,7-20, 8-20, 9-20, 10-20, 11-20, 12-20, 13-20, 14-20, or 15-20. 
     In some embodiments, M 1  comprises an integrin-binding compound. In some embodiments, the integrin-binding compound comprises an α v β 3 -binding compound. In some embodiments, the integrin-binding compound comprises an RGD ligand. In some embodiments, the α v β 3 -binding compound comprises an RGD ligand. In some embodiments the RGD ligand comprises an RGD mimic. In some embodiments, the steric stabilizer comprises a polyethylene glycol (PEG). In some embodiments, cleavage of L 1  and/or L 2  restores an unmodified amine on P. In some embodiments, (L 1 -M 1 ) and (L 2 -M 2 ) are independently tetrapeptide modifying agents and/or dipeptide modifying agents. In some embodiments, L 1  and L 2  are independently tetrapeptide linkages or dipeptide-PABC (p-amidobenzyl-carbamate) linkages. In some embodiments, L 1  and L 2  are tetrapeptide linkages. In other embodiments, L 1  and L 2  are dipeptide-PABC linkages. In some embodiments, L 1  is a dipeptide-PABC linkage and L 2  is a tetrapeptide linkage. In other embodiments, L 1  is a tetrapeptide linkage and L 2  is a dipeptide-PABC linkage. In some embodiments, a tetrapeptide linkage is an FCitFP (Phenylalanine-Citrulline-Phenylalanine-Proline) tetrapeptide linkage. In some embodiments, a dipeptide-PABC linkage is an ACit-PABC linkage. For x=2 or more, L can be all tetrapeptide linkages, all dipeptide-PABC linkages, or a combination tetrapeptide linkages and dipeptide-PABC linkages. For y=2 or more, L 2  and be all tetrapeptide linkages, all dipeptide-PABC linkages, or a combination tetrapeptide linkages and dipeptide-PABC linkages. 
     In some embodiments, a described Hif2α RNAi trigger is conjugated to a reversibly modified membrane active polyamine to form an RNAi trigger-delivery polymer conjugate. In some embodiments, the RNAi trigger-delivery polymer conjugate comprises the formula represented by: 
       (RNAi trigger) n -poly(A a -co-(B b -graft-(C c ;D d )))  (formula 2)
         wherein   A is a hydrophobic group-containing monomeric unit,   B is a primary amine-containing monomeric unit,   C comprises an integrin-binding ligand linked (i.e., grafted) to a primary amine-containing monomeric unit via a reversible physiologically labile linkage,   D comprises a steric stabilizer linked (i.e., grafted) to a primary amine-containing monomeric unit via a reversible physiologically labile linkage,   a is an integer greater than zero,   b is an integer greater than or equal to two,   c is an integer greater than or equal to one,   d is an integer greater than or equal to one,   the value of c+d is greater than 80%, greater than 85%, greater than 90%, or greater than 95% of the value of b,   poly(A a -co-B b ) is a membrane active polyamine copolymer having A and B monomeric units RNAi trigger comprises a Hif2α RNAi trigger described herein, and n has a value from 0.25 (i.e., conjugated to only one out of every four delivery polymers) to 5.0.       

     Poly(A a -c(B b -graft-(C c ; D d ))) is not membrane active. In some embodiments, the integrin-binding compound comprises an α v β 3 -binding compound. In some embodiments, the integrin-binding compound comprises an RGD ligand, such as an RGD mimic. In some embodiments, the α v β 3 -binding compound comprises an RGD ligand, such as an RGD mimic. In some embodiments, the steric stabilizer comprises a polyethylene glycol (PEG). In some embodiments, the PEG contains 2 to 25 ethylene glycol units. In some embodiments, c is any integer from 1-75, 1-50, 5-50, 5-40, 5-30, 5-25, 5-20, 5-15, 10-35, 10-30, 10-25, 10-20, or 15-20. In some embodiments, n has a value from 0.5 to 2. In some embodiments, the ratio A:B (i.e., a:b) is 30:70 to 60:40. In some embodiments, the ratio A:B is 60:40 to 40:60. In some embodiments, the ratio A:B is about 45+5:55+5. In some embodiments, the ratio A:B is about 44:56. In some embodiments, the ratio A:B is about 46:54. In some embodiments, the molecular weight (Mw) of the polymer is 30 kDa-70 kDa. In other embodiments, the Mw of the polymer is 40 kDa-60 kDa. In other embodiments, the Mw of the polymer is 40 kDa-50 kDa. In yet other embodiments, the Mw of the polymer about 43 kDa to about 48 kDa. In some embodiments, the polymer has a polydispersity index (PDI) less than 1.4, less than 1.3, 1.25, less than 1.2, less than 1.15, or less than 1.1. In some embodiments, the polymer contains a terminal azide group for attachment of an RNAi trigger. In some embodiments, n is 0.8-1.6. In some embodiments, n is 1+0.5. In some embodiments, c is 1-20, 2-20, 3-20, 4-20, 5-20, 6-20, 7-20, 8-20, 9-20, 10-20, 11-20, 12-20, 13-20, 14-20, or 15-20. In some embodiments, the value of c+d is greater than 80%, greater than 90%, or greater than 95% of the value of b. In some embodiments, C is RGD-PEG x -FcitFPro and D is PEG y -ACit-PABC, wherein x is 1-50, y is 4-30. In some embodiments, x is greater than y. 
     In some embodiments, polyamine poly(A a -co-B b ) is a poly(acrylate) random copolymer wherein A is a hydrophobic group-containing acrylate monomer and B is a primary amine-containing acrylate monomer. In some embodiments A is a propyl acrylate monomer and B is an ethoxy-ethylamine acrylate monomer. 
     Membrane active polyamines are membrane active and therefore capable of disrupting plasma membranes or lysosomal/endocytic membranes. As used herein, membrane active polyamines are surface active, amphipathic polymers that are able to induce one or more of the following effects upon a biological membrane: an alteration or disruption of the membrane that allows non-membrane permeable molecules to enter a cell or cross the membrane, pore formation in the membrane, fission of membranes, or disruption or dissolving of the membrane. As used herein, a membrane, or cell membrane, comprises a lipid bilayer. The alteration or disruption of the membrane can be functionally defined by the peptide&#39;s activity in at least one the following assays: red blood cell lysis (hemolysis), liposome leakage, liposome fusion, cell fusion, cell lysis, and endosomal release. Peptides, or modified peptides that preferentially cause disruption of endosomes or lysosomes over plasma membranes are considered endosomolytic. A reversibly modified membrane active polyamine is an example of an endosomolytic peptide. The effect of membrane active polymers on a cell membrane may be transient. Membrane active polymers possess affinity for the membrane and cause a denaturation or deformation of bilayer structures. Delivery of a RNAi trigger to a cell is mediated by the membrane active polyamine disrupting or destabilizing the plasma membrane or an internal vesicle membrane (such as an endosome or lysosome), including forming a pore in the membrane, or disrupting endosomal or lysosomal vesicles thereby permitting release of the contents of the vesicle into the cell cytoplasm. A preferred polymer is an amphipathic poly(acrylate) random copolymer. 
     Integrin-Binding Compound 
     An integrin-binding compound has affinity for one or more integrins expressed on a cell surface. A non-limiting example of an integrin includes an α v β 3  integrin. Examples of integrin-binding compounds include, but are not limited to: α v β 3 -binding compounds, RGD ligand. RGD ligands include RGD peptide-containing compounds and RGD mimic-containing compounds. As used herein, an RGD peptide comprises an arginine-glycine-aspartate tripeptide. An RGD peptide may be conformationally constrained. An RGD peptide may have non-peptide components linked to the RGD amino acid sequence. 
     As used herein, an RGD ligand comprises an RGD peptide or RGD mimic&lt;1500 kDa in size that binds to (has affinity for) an integrin, such as an alpha v/beta 3 (αvβ3 or α v β 3 ) integrin. 
     As used herein, an RGD mimic is a non-peptide synthetic molecule other than an RDG peptide that biologically mimics the active determinants of an RGD peptide, an integrin-binding RGD portion of an integrin-binding protein, or an α v β 3  integrin-binding RGD motif. An RGD mimic may contain one or two naturally occurring amino acids linked via amide bonds. An RGD mimetic may be a modified peptide, contain non-standard amino acids or non-standard amino acid side chains. 
     In one embodiment, an RGD ligand comprises a guanidinium group linked to a glycine-aspartate dipeptide via an amide bond. Guanidinium groups of the invention have the structure represented by: 
     
       
         
         
             
             
         
       
     
     wherein R 9  and R 10  are independently hydrogen or alkyl and may by connected to form a ring, and R 11  is a linker connecting the guanidinium group to the glycine-aspartate dipeptide. The guanidinium group includes both the structure represented above and its resonance structures. A preferred linker is: —(CRR′)—(CRR′HCRR′)— or —(CRR′)—(CRR′)—(CRR′)—(CRR′)—, wherein: a) each R is independently optional and if present is independently hydrogen, alkyl, or aryl, b) R′ is independently hydrogen, alkyl, aryl, or NH2, and c) each carbon (C) may be linked by single bonds, a single bond and a double bond, or aromatic bonds. 
     In some embodiments, an RGD mimic contains a phenoxy group attached to the aspartate amino acid. In some embodiments, an RGD mimic comprises a quanidinium-glycine-aspartate-4-aminophenoxy compound. In some embodiments, a quanidinium-glycine-aspartate-4-aminophenoxy compound comprises the structure represented by: 
     
       
         
         
             
             
         
       
     
     wherein R D  is: 
     
       
         
         
             
             
         
       
     
     In some embodiments, a guanidinium is 
     
       
         
         
             
             
         
       
     
     and their resonance structures. 
     In some embodiments, an RGD mimic comprises the structure represented by: 
     
       
         
         
             
             
         
       
         
         
           
             wherein:
           R 14  is   
         
           
         
       
    
     
       
         
         
             
             
         
       
     
     and 
     A comprises a linker. The linker connects the RGD mimic to another molecule such as a dipeptide amidobenzyl-carbonate or tetrapeptide, provides for increased solubility, or provides a means for covalent linkage to another molecule. 
     Steric Stabilizer 
     As used herein, a steric stabilizer is a non-ionic hydrophilic polymer (either natural, synthetic, or non-natural) that prevents or inhibits intramolecular or intermolecular interactions of a polymer to which it is attached relative to the polymer containing no steric stabilizer. A steric stabilizer hinders a polymer to which it is attached from engaging in electrostatic interactions. Electrostatic interaction is the non-covalent association of two or more substances due to attractive forces between positive and negative charges. Steric stabilizers can inhibit interaction with blood components and therefore opsonization, phagocytosis, and uptake by the reticuloendothelial system. Steric stabilizers can thus increase circulation time of molecules to which they are attached. Steric stabilizers can also inhibit aggregation of a polymer. In some embodiments, a steric stabilizer is a polyethylene glycol (PEG) or PEG derivative. In some embodiments, a PEG can have about 1-500 ethylene monomers or units. In some embodiments, the PEG contains 2-25 ethylene units. In some embodiments, the PEG contains 4-30 ethylene units. In some embodiments, PEG contains 5-24 ethylene units. In some embodiments, a PEG has a molecular weight average of about 85-20,000 Daltons (Da). In some embodiments a PEG has a molecular weight of about 85-1000 Da. As used herein, steric stabilizers prevent or inhibit intramolecular or intermolecular interactions of a polymer to which it is attached relative to the polymer containing no steric stabilizer in aqueous solution. 
     Reversible Physiologically Labile Linkages/Modifying Agents 
     A membrane active polyamine may be reversibly modified. Reversible modification can be accomplished through reversible attachment of modifying agents to primary amines of the membrane active polyamine. 
     In some embodiments, a reversible physiologically labile linkage comprises a tetrapeptide linkage. In some embodiments, P-(L 1 -M 1 ) x  and/or P-(L 2 -M 2 ) y  (of formula 1) comprises: 
       R 5 -A 4 -A 3 -A 2 -A 1 -R 6    
     wherein
         R 5  comprises a targeting group (M) or a steric stabilizer (M 2 ),   A 4  is a natural, non-natural isomeric, or synthetic hydrophobic L amino acid wherein the hydrophobicity index (Monera et al, J. Protein Sci. 1995, 1, 319) at pH 7 is 41 or greater, normalized to glycine, as it relates to the composition of the amino acid side chain (R-group),   A 3  is an uncharged hydrophilic L amino acid wherein the hydrophobicity index (Monera et al, J. Protein Sci. 1995, 1, 319) at pH 7 is −28 or less, normalized to glycine, as it relates to the composition of amino acid side chain (R-group),   A 2  is a natural, non-natural isomeric, or synthetic hydrophobic L amino acid wherein the hydrophobicity index (Monera et al, J. Protein Sci. 1995, 1, 319) at pH 7 is 41 or greater, normalized to glycine, as it relates to the composition of the amino acid side chain (R-group),   A 1  is L-proline, L-leucine, or L-N-methyl alanine, and   R 6  is P, wherein P is a membrane active polyamine of formula 1.       

     In some embodiments, A 1  is proline, A 2  and A 4  are independently alanine, valine, leucine, isoleucine or phenylalanine (side chains of —CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , or —CH 2 C 6 H 6 , respectively), and A 3  is citrulline or asparagine (side chains or —(CH 2 ) 3 NHCONH 2  or —CH 2 CONH 2 , respectively). 
     In some embodiments, A 1  is proline, A 2  and A 4  are phenylalanine, and A 3  is citrulline (FCitFPro). In some embodiments, A 1  is proline, A 2  is phenylalanine, and A 3  is citrulline, and A 4  is alanine (ACitFPro). 
     In some embodiments, a tetrapeptide modifying agent has the structure represented by: 
     
       
         
         
             
             
         
       
         
         
           
             wherein, 
             R 5  comprises a targeting group (M) or a steric stabilizer (M 2 ), 
             R4 is a side chain of a natural, non-natural isomeric, or synthetic hydrophobic amino acid, 
             R 3  is a side chain of an uncharged hydrophilic amino acid, preferably citrulline, 
             R 2  is a side chain of a natural, non-natural isomeric, or synthetic hydrophobic amino acid, preferably phenylalanine, 
             X and Y are:
           a) (CH 2 ) 2 (CH 3 ) 2  and H, respectively (tetrapeptide A′ is Leucine),   b) CH 3 — and CH 3 —, respectively (tetrapeptide A′ is N-methyl alanine), or   c) CH 2 — and CH 2 —CH 2 —, respectively (tetrapeptide A′ is proline); and   
         
             R is 
           
         
       
    
     
       
         
         
             
             
         
       
     
     Reaction of the tetrapeptide modifying agent with a polyamine yields P-(L-M). 
     In some embodiments, R4 is a side chain of phenylalanine or alanine. In some embodiments, R 3  is a side chain of citrulline. In some embodiments, R 2  is a side chain of phenylalanine. 
     In some embodiments, the membrane active polyamine is modified with dipeptide modifying agents (dipeptide-PABC-PNP modifying agent) having the general form: 
       R-A 1 A 2 -amidobenzyl-carbonate. 
     wherein R comprises a steric stabilizer or targeting group, A 1  is a hydrophobic amino acid, and A 2  is a hydrophilic uncharged amino acid. Reaction of the modifying agent carbonate with a polymer amine yields a carbamate linkage. In some embodiments, the amidobenzyl group is a p-amidobenzyl group. In some embodiments, the carbonate is an activated amine reactive carbonate. In some embodiments, dipeptide-PABC cleavable linkers have the general structure: 
     
       
         
         
             
             
         
       
     
     wherein R4 comprises a targeting group or steric stabilizer, R3 comprises an amine reactive carbonate moiety, such as a para-nitrophenyl group, R1 is the side chain of a hydrophobic amino acid, such as Phenylalanine or Alanine and R2 is the side chain of a hydrophilic uncharged are amino acid, such as citrulline (Cit). In some embodiments, R1 is the side chain of Phenylalanine or Alanine. In some embodiments, R2 is the side chain of citrulline (Cit). 
     In some embodiments, an RGD modifying agent comprises the structure represented by: 
     
       
         
         
             
             
         
       
     
     wherein R 14  is a guanidinium-containing group as defined above, A 1  comprises a PEG-containing linker, R 1  is a side chain of a Phenylalanine or Alanine, R 2  is a side chain of citrulline, and R 3  is an amine-reactive carbonate. 
     A delivery polymer can include a polyamine reversibly modified by reaction of primary amines on the polymer with a disubstituted alkylmaleic anhydride: 
     
       
         
         
             
             
         
       
     
     wherein R1 comprises a targeting group or a steric stabilizer. 
     In some embodiments, the disubstituted alkylmaleic anhydride has the structure represented by: 
     
       
         
         
             
             
         
       
     
     wherein R1 comprises an targeting group or a steric stabilizer. 
     In some embodiments, a targeting group (e.g., RGD ligand) is linked to a modifying agent via a linker, such as a PEG linker. The PEG linker can have 1-50 ethylene units. 
     RGD and PEG modifying agents are shown in  FIGS. 1-7 . 
     In some embodiments, we describe compositions represented by the formula: 
     
       
         
         
             
             
         
       
     
     wherein: RNAi trigger is an Hif2α RNAi trigger, n is 0.5-5, P is a membrane active polyamine, L 1 -M 1  comprises RGD-PEG a -FCitFPro-, a is 1-50, x is 1-20, L 2 -M 2  comprises PEG b -ACit-PABC-, b is 4-30, and y is greater than or equal to 0, and (M 2 -L 2 ) y -P-(L-M). is not membrane active. In some embodiments, the value of x+y is greater than 80%, greater than 90%, or greater than 95% of the number of primary amines of P. In some embodiments, n is 0.5-2. In some embodiments, n is 0.8-1.6. In some embodiments, x is 2-20, 3-20, 4-20, 5-20, 6-20, 7-20, 8-20, 9-20, 10-20, 11-20, 12-20, 13-20, 14-20, or 15-20. In some embodiments, the value of a is greater than the value of b. 
     Pharmaceutical Compositions 
     In some embodiments, at least one of the described Hif2α RNAi triggers is used in the preparation of a pharmaceutical composition (i.e., medicament) for treatment of a subject that would benefit from reduction or inhibition in Hif2α expression. These pharmaceutical compositions are useful in the inhibition of the expression of the Hif2α gene in a cell, a tissue, or an organism. In some embodiments, the described pharmaceutical compositions are used to treat a subject having a disease or disorder that would benefit from reduction or inhibition in Hif2α expression. 
     As used herein, a pharmaceutical composition or medicament comprises a pharmacologically effective amount of at least one of the described Hif2α RNAi triggers or Hif2α RNAi trigger-containing conjugates and one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients (excipients) are substances other than the Active Pharmaceutical ingredient (API, therapeutic product, e.g., RNAi trigger) that have been appropriately evaluated for safety and are intentionally included in the drug delivery system. Excipients do not exert or are not intended to exert a therapeutic effect at the intended dosage. Excipients may act to a) aid in processing of the drug delivery system during manufacture, b) protect, support or enhance stability, bioavailability or patient acceptability of the API, c) assist in product identification, and/or d) enhance any other attribute of the overall safety, effectiveness, of delivery of the API during storage or use. A pharmaceutically acceptable excipient may or may not be an inert substance. 
     Excipients include, but are not limited to: absorption enhancers, anti-adherents, anti-foaming agents, anti-oxidants, binders, binders, buffering agents, carriers, coating agents, colors, delivery enhancers, dextran, dextrose, diluents, disintegrants, emulsifiers, extenders, fillers, flavors, glidants, humectants, lubricants, oils, polymers, preservatives, saline, salts, solvents, sugars, suspending agents, sustained release matrices, sweeteners, thickening agents, tonicity agents, vehicles, water-repelling agents, and wetting agents. 
     A pharmaceutical composition can contain other additional components commonly found in pharmaceutical compositions. Such additional components include, but are not limited to: anti-pruritics, astringents, local anesthetics, or anti-inflammatory agents (e.g., antihistamine, diphenhydramine, etc.). It is also envisioned that cells, tissues or isolated organs that express or comprise the herein defined RNAi triggers may be used as “pharmaceutical compositions”. As used herein, “pharmacologically effective amount,” “therapeutically effective amount,” or simply “effective amount” refers to that amount of an RNAi trigger to produce the intended pharmacological, therapeutic or preventive result. 
     In some embodiments, a described Hif2α RNAi trigger is combined one or more additional therapeutics or treatments including, but not limited to: a second Hif2α RNAi trigger or other RNAi agent, a small molecule drug, an antibody, an antibody fragment, and/or a vaccine. 
     The described RNAi triggers and pharmaceutical compositions comprising Hif2α RNAi triggers disclosed herein may be packaged or included in a kit, container, pack, or dispenser. The Hif2α RNAi triggers and pharmaceutical compositions comprising said Hif2α RNAi triggers may be packaged in pre-filled syringes or vials. 
     Cells, tissues, and non-human organisms that include at least one of the Hif2α RNAi triggers described herein is contemplated. The cell, tissue, or non-human organism is made by delivering the RNAi trigger to the cell, tissue, or non-human organism by any means available in the art. In some embodiments, the cell is a mammalian cell, including, but no limited to, a human cell. The cell, tissue, or non-human organisms are useful for research or as research tools (e.g., drug testing or diagnoses). 
     Method of Treatment 
     In some embodiments, the Hif2α RNAi triggers described herein are used to treat a subject having a disease or disorder that would benefit from reduction or inhibition in Hif2α expression. In some embodiments, the described Hif2α RNAi triggers are used to treat or prevent at least one symptom in a subject having a disease or disorder that would benefit from reduction or inhibition in Hif2α expression. The subject is administered a therapeutically effective amount of any one or more of the described RNAi triggers thereby treating the symptom. 
     In some embodiments, the Hif2α RNAi triggers are used to treat or manage a clinical presentation wherein a subject in need of such treatment, prevention or management is administered a therapeutically or prophylactically effective amount of one or more of the Hif2α RNAi triggers or Hif2α RNAi trigger-containing compositions described herein. In some embodiments, the method comprises administering a composition comprising an Hif2α RNAi trigger molecule described herein to a mammal to be treated. 
     Representative diseases that would benefit from a reduction and/or inhibition of Hif2α gene expression include, but are not limited to, cancer, renal cancer, clear cell renal cell carcinoma, non-small cell lung cancer, astrocytoma (brain cancer), bladder cancer, breast cancer, chondrosarcoma, colorectal carcinoma, gastric carcinoma, glioblastoma, head and neck squamous cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, neuroblastoma, melanoma, multiple myeloma, ovarian cancer, rectal cancer, metastases, gingivitis, psoriasis, Kaposi&#39;s sarcoma-associated herpesvirus, preeclampsia, inflammation, chronic inflammation, neovascular diseases, and rheumatoid arthritis. 
     In some embodiments, an Hif2α RNAi trigger can be used to inhibit expression of Hif2α in a cell, group of cells, or a tissue, e.g., in a subject. In some embodiments, an Hif2α RNAi trigger can be used to formulate a composition for inhibiting expression of Hif2α in a cell, group of cells, or a tissue, e.g., in a subject. In some embodiments, a therapeutically effective amount of one type (or several different types) of Hif2α RNAi triggers as described herein is administered to a subject, thereby inhibiting expression of Hif2α in the subject (e.g., an amount effective to inhibit expression of Hif2α in the subject). 
     As used herein, the terms “silence,” “reduce,” “inhibit,” “down-regulate,” or “knockdown gene expression,” when referring to an Hif2α gene, mean that the expression of the gene, as measured by the level of RNA transcribed from the gene or the level of polypeptide, protein, or protein subunit translated from the mRNA in a cell, group of cells, or tissue, in which the Hif2α gene is transcribed, is reduced when the cell, group of cells, or tissue, is treated with the described Hif2α RNAi triggers as compared to a second cell, group of cells, or tissue that has or has not been so treated or compared to the same cell, group of cells, or tissue, prior to administration of the Hif2α RNAi trigger. 
     In some embodiments, the gene expression level and/or mRNA level of Hif2α in a subject to whom a described Hif2α RNAi trigger is administered is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98% relative to the subject prior to being administered the Hif2α RNAi trigger or to a subject not receiving the Hif2α RNAi trigger. The gene expression level and/or mRNA level in the subject may be reduced in a cell, group of cells, and/or tissue of the subject. In some embodiments, the protein level of Hif2α in a subject to whom a described Hif2α RNAi trigger has been administered is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98% relative to the subject prior to being administered the Hif2α RNAi trigger or to a subject not receiving the Hif2α RNAi trigger. The protein level in the subject may be reduced in a cell, group of cells, tissue, blood, and/or other fluid of the subject. A reduction in gene expression, mRNA, or protein levels can be assessed by any methods known in the art. Reduction or decrease in Hif2α mRNA level and/or protein level are collectively referred to herein as a reduction or decrease in Hif2α or inhibiting or reducing the expression of Hif2α. 
     “Introducing into a cell”, when referring to an RNAi trigger, means functionally delivering the RNAi trigger into a cell. By functional delivery, it is meant that the RNAi trigger is delivered to the cell and has the expected biological activity, (e.g., sequence-specific inhibition of gene expression). 
     The route of administration is the path by which an RNAi trigger is brought into contact with the body. In general, methods of administering drugs and nucleic acids for treatment of a subject are well known in the art and can be applied to administration of the compositions described herein. The compounds described herein can be administered via any suitable route in a preparation appropriately tailored to the particular route. Thus, the compounds described herein can be administered by injection, for example, intravenously, intramuscularly, intracutaneously, subcutaneously, or intraperitoneally. 
     In some embodiments, the Hif2α RNAi trigger molecules or compositions described herein can be delivered to a cell, group of cells, tissue, or subject using oligonucleotide delivery technologies known in the art. In general, any suitable method recognized in the art for delivering a nucleic acid molecule (in vitro or in vivo) can be adapted for use with an Hif2α RNAi trigger described herein. For example, delivery can be by local administration, (e.g., direct injection, implantation, or topical administering), systemic administration, or subcutaneous, intravenous, oral, intraperitoneal, or parenteral routes, including intracranial (e.g., intraventricular, intraparenchymal and intrathecal), intramuscular, transdermal, airway (aerosol), nasal, rectal, or topical (including buccal and sublingual) administration, In certain embodiments, the compositions are administered by subcutaneous or intravenous infusion or injection. 
     The above provided embodiments and items are now illustrated with the following, non-limiting examples. 
     EXAMPLES 
     Example 1. RNAi Trigger Synthesis 
     A) Synthesis. RNAi trigger molecules were synthesized according to phosphoramidite technology on solid phase used in oligonucleotide synthesis. Depending on the scale either a MerMade96E (Bioautomation) or a MerMade12 (Bioautomation) was used. Syntheses were performed on a solid support made of controlled pore glass (CPG, 500 Å or 600 Å, obtained from Prime Synthesis, Aston, Pa., USA). All DNA, 2′-modified RNA, and UNA phosphoramidites were purchased from Termo Fisher Scientific (Milwaukee, Wis., USA). Specifically, the following 2′-O-Methyl phosphoramidites were used: (5′-O-dimethoxytrityl-N 6 -(benzoyl)-2′-O-methyl-adenosine-3′-O-(2-cyanoethyl-N,N-diisopropy-lamino) phosphoramidite, 5′-O-dimethoxy-trityl-N 4 -(acetyl)-2′-O-methyl-cytidine-3′-O-(2-cyanoethyl-N,N-diisopropyl-amino) phosphoramidite, (5′-O-dimethoxytrityl-N 2 -(isobutyryl)-2′-O-methyl-guanosine-3′-O-(2-cyano-ethyl-N,N-diisopropylamino)phosphoramidite, and 5′-O-dimethoxy-trityl-2′-O-methyl-uridine-3′-O-(2-cyanoethyl-N,N-diisopropylamino)phosphoramidite. The 2′-Deoxy-2′-fluoro-phosphor-amidites carried the same protecting groups as the 2′-O-methyl RNA amidites. The following UNA phosphoramidites were used: 5′-(4,4′-Dimethoxytrityl)-N-benzoyl-2′,3′-seco-adenosine, 2′-benzoyl-3′-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphor-amidite, 5′-(4,4′-Dimethoxytrityl)-N-acetyl-2′,3′-seco-cytosine, 2′-benzoyl-3′-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5′-(4,4′-Dimethoxytrityl)-N-isobutyryl-2′,3′-seco-guanosine, 2′-benzoyl-3′-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, and 5′-(4,4′-Dimethoxy-trityl)-2′,3′-seco-uridine, 2′-benzoyl-3′-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite. All amidites were dissolved in anhydrous acetonitrile (50 mM) and molecular sieves (3 Å) were added. In order to introduce the TEG-Cholesterol at the 5′-end of the oligomers, the 1-Dimethoxytrityloxy-3-O—(N-cholesteryl-3-aminopropyl)-triethyleneglycol-glyceryl-2-O-(2-cyanoethyl)-(N,N,-diisopropyl)-phosphoramidite from Glen Research (Sterling, Va., USA) was employed. The 5′-modifications were introduced without any modification of the synthesis cycle. 5-Benzylthio-1H-tetrazole (BTT, 250 mM in acetonitrile) was used as activator solution. 
     Coupling times were 10 min (RNA), 180 sec (Cholesterol), 90 sec (2′OMe and UNA), and 60 sec (2′F and DNA). In order to introduce phosphorothioate linkages, a 100 mM solution of 3-phenyl 1,2,4-dithiazoline-5-one (POS, obtained from PolyOrg, Inc., Leominster, Mass., USA) in anhydrous Acetonitrile was employed. See Tables 1-2 and 5 for specific sequences. 
     B. Cleavage and deprotection of support bound oligomer. After finalization of the solid phase synthesis, the dried solid support was treated with a 1:1 volume solution of 40 wt. % methylamine in water and 28% ammonium hydroxide solution (Aldrich) for two hours at 30° C. The solution was evaporated and the solid residue was reconstituted in water (see below). 
     C. Purification. Crude Cholesterol containing oligomers were purified by reverse phase HPLC using a Waters XBridge BEH300 C4 5u Prep column and a Shimadzu LC-8 system. Buffer A was 100 mM TEAA, pH 7.5 and contained 5% Acetonitrile and buffer B was 100 mM TEAA and contained 95% Acetonitrile. UV traces at 260 nm were recorded. Appropriate fractions were then run on size exclusion HPLC using a GE Healthcare XK 16/40 column packed with Sephadex G-25 medium with a running buffer of 100 mM ammonium bicarbonate, pH 6.7 and 20% Acetonitrile. Other crude oligomers were purified by anionic exchange HPLC using a TKSgel SuperQ-5PW 13u column and Shimadzu LC-8 system. Buffer A was 20 mM Tris, 5 mM EDTA, pH 9.0 and contained 20% Acetonitrile and buffer B was the same as buffer A with the addition of 1.5 M sodium chloride. UV traces at 260 nm were recorded. Appropriate fractions were pooled then run on size exclusion HPLC as described for cholesterol containing oligomers. 
     D. Annealing. Complementary strands were mixed by combining equimolar solutions (sense and antisense) in 0.2×PBS (Phosphate-Buffered Saline, 1×, Corning, Cellgro) to form the RNAi triggers. This solution was placed into a thermomixer at 70° C., heated to 95° C., held at 95° C. for 5 min, and cooled to room temperature slowly. Some RNAi triggers were lyophilized and stored at −15 to −25° C. Duplex concentration was determined by measuring the solution absorbance on a UV-Vis spectrometer in 0.2×PBS. The solution absorbance at 260 nm was then multiplied by a conversion factor and the dilution factor to determine the duplex concentration. Unless otherwise stated, all conversion factor was 0.037 mg/(mL cm). For some experiments, a conversion factor was calculated from an experimentally determined extinction coefficient. 
     Example 2. Synthesis of APN 1170-100A (100A). APN 1203-006 (006). APN 1203-064 (064) Amphipathic Membrane Active Polyamines 
       
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
               
               
                   
                 MW 
                 Theoretical MW 
                   
                 % Amine 
                 % Alkyl 
                 % End Group 
                 Azides/ 
               
               
                 Polymer 
                 (protected) 
                 (deprotected) 
                 PDI 
                 Incorp. 
                 Incorp. 
                 Removal 
                 Polymer 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 APN 1170-100A 
                 64,430 
                 45,765 
                 1.22 
                 56 
                 44 
                 0 
                 1.25 
               
               
                 APN 1203-006 
                 60,330 
                 43,578 
                 1.05 
                 56 
                 44 
                 99 
                 1.14 
               
               
                 APN 1203-062 
                 65,170 
                 46,736 
                 1.05 
                 54 
                 46 
                 99 
                 0.96 
               
               
                   
               
            
           
         
       
     
     A. Materials. 2,2′-Azobis(2,4-dimethyl valeronitrile) (V-65, radical initiator) was purchased from Wako Pure Chemical Industries. Propyl acrylate was purchased from Polysciences Inc. N-Boc-ethoxy-ethylamine acrylate was obtained from WuXi Inc. 2-(Dodecylthio-carbonothioylthio)-2-methylpropionic acid (DDMAT, RAFT Agent), 1,1′-Azobis-(cyclo-hexanecarbonitrile) (ACHN), 1-Ethylpiperidine hypophosphite (EPHP), Pentafluorophenol, N,N′-Dicyclohexylcarbodiimide and N,N-diisopropyl-ethylamine were purchased from Sigma Aldrich. O-(2-Aminoethyl)-O′-(2-azidoethyl)triethylene Glycol (azido-PEG 4 -amine) was purchased from Biomatrik Inc. 
     B. RAFT copolymer of N-Boc-ethoxyethylamine acrylate and propyl acrylate (EAP). Solutions of V-65 (2 mg/mL) and RAFT agent DDMAT (10 mg/mL) in butyl acetate were prepared. Monomer molar feed was 52% N-Boc-ethoxyethylamine acrylate, 48% propyl acrylate. Theoretical Mw was 75,000. RAFT agent (DDMAT) to initiator (V-65) molar ratio was 6.67:1. 
     N-Boc-ethoxyethylamine acrylate (1.778 g, 6.86 mmol), propyl acrylate (0.794 mL, 0.722 g, 6.33 mmol), DDMAT solution (1.215 mL, 0.0333 mmol), V-65 solution (0.621 mL, 0.005 mmol), and butyl acetate (10.2 mL) were added to a 20 mL glass vial with a stir bar. The vial was sealed with a septa cap and the solution bubbled with nitrogen using a long needle with a second needle as the outlet for 1 h. The needles were removed and the vial was heated to 50° C. for 24 h with stirring. The solution was allowed to cool to room temperature and transferred equally between two 50 mL centrifuge tube before hexane (35 mL) was added to both tubes. The solution was centrifuged for 2 min at 4400 rpm. The supernatant layer was carefully decanted and the bottom layer rinsed with hexane. The bottom layer of each tube was then re-dissolved in dichloromethane (7 mL), precipitated in hexane (40 mL) and centrifuged once more. The supernatant was decanted and the bottom layer rinsed with hexane before the layers were combined to one 50 mL centrifuge tube and the polymer was dried under reduced pressure for several hours. The yield of crude EAP copolymer was 2.1 g. Samples of the copolymer were taken for multi-angle light scattering (MALS), and  1 H-NMR.
         Polymer 006: The composition determined by  1 H-NMR was 55% N-Boc-ethoxyethylamine acrylate and 45% propyl acrylate. The Mw for 006 determined by MALS was 58,600 g/mol with a polydispersity index (PDI) of 1.04.   Polymer 100A: Composition by 1H-NMR: 56% N-Boc-ethoxyethylamine acrylate and 44% propyl acrylate. MW by MALS: 65,150, PDI of 1.122.   Polymer 064: Composition by 1H-NMR: 54% N-Boc-ethoxyethylamine acrylate and 46% propyl acrylate. The Mw for 064 determined by MALS was 57,957 g/mol with a polydispersity index (PDI) of 1.07.       

     C. Radical induced w-end group removal (polymers 006 and 064). Solutions of 1,1′-Azobis-(cyclohexanecarbonitrile) (ACHN, 20 mg/mL) and 1-Ethylpiperidine hypophosphite (EPHP, 100 mg/mL) were prepared in toluene. EAP (2 g, 0.035 mmol), ACHN (0.213 mL, 0.5 eq, 0.0174 mmol), EPHP (1.25 mL, 20 eq, 0.697 mmol), and toluene (25.2 mL) were added to a 40 mL glass vial with a stir bar. The vial was sealed with a septa cap and the solution bubbled with nitrogen using a long needle with a second needle as the outlet for 1 h. The needles were removed and the vial was heated to 100° C. for 2 h. The solution was allowed to cool to room temperature and −20 mL toluene was removed by rotary evaporation. The remaining solution was transferred to a 50 mL centrifuge vial, and hexane (35 mL) was added. The solution was centrifuged for 2 min at 4400 rpm. The supernatant layer was carefully decanted and the bottom layer rinsed with hexane. The bottom layer was then re-dissolved in dichloromethane (7 mL), precipitated in hexane (40 mL) and centrifuged once more. The supernatant was decanted and the bottom layer rinsed with hexane before the polymer was dried under reduced pressure for ˜1 h. The polymer was dissolved in methyl tert-butyl ether (80 mL) and transferred to a separatory funnel. The solution was then washed with 3×30 mL volumes of H 2 O followed by 3×30 mL volumes of saturated NaCl. The polymer solution was then dried over sodium sulfate, and vacuum filtered through 0.45 μm GHP filters. MTBE was removed via rotary evaporation and high vacuum. A sample was taken for monitoring of end group removal using a UV spectrophotometer. End group removal was calculated to be 99%. Samples were taken for MALS, GC-FID, and  1 H-NMR. The composition of 006 by H-NMR was 55% N-Boc-eth oxyethylamine acrylate and 45% propyl acrylate. The conversion of 006 determined by GC-FID was 81.4% for the N-Boc-ethoxyethylamine acrylate and 77.3% for the propyl acrylate. The conversion of 100A determined by GC-FID conversion was 87% for N-Boc-ethoxyethylamine acrylate and 83% for propyl acrylate. The Mw for polymer 006 determined by MALS was 57,700 g/mol with a polydispersity index (PDI) of 1.06. 
     D. Pentafluorophenol activation of α-end group. EAP polymer (2 g, 0.0347 mmol), pentafluorophenol (63.8 mg, 0.3466 mmol), N,N′-Dicyclohexylcarbodiimide (71.5 mg, 0.3466 mmol), and dichloromethane (40 mL) were added to a 100 mL round bottom flask with a stir bar. The flask was stoppered with a rubber septum and the system was purged with nitrogen for 15 min. The solution was stirred for 16 h at room temperature. Additional Pentafluorophenol (63.8 mg, 0.3466 mmol) and N,N′-Dicyclohexylcarbodiimide (71.5 mg, 0.3466 mmol) were added, the flask stoppered with a rubber septum, and the system was purged with nitrogen for 15 min. The solution was stirred for 3 h at room temperature. The polymer was precipitated with hexane (˜10× volume), centrifuged, and the solvent was decanted. The polymer was dissolved in minimal dichloromethane, precipitated with hexane (˜10× volume), centrifuged, and the solvent was decanted. The polymer was dissolved in minimal ethyl acetate, precipitated with hexane (˜10× volume), centrifuged, and the solvent was decanted. The polymer precipitate was dried under high vacuum until the solid reached a constant weight. 
     E. Azide functionalization of α-end group. In a 100 ml round bottom flask equipped with a rubber septum and stir bar, polymer from the previous step (1.9 g, 0.0329 mmol) was dissolved in dichloromethane (38 mL). Azido-PEG 4 -Amine (86.4 mg, 0.3293 mmol) and N,N-Diisopropylethylamine (46.8 mg, 63.1 μL, 0.3622 mmol) were added to the flask with stirring. The system was purged with nitrogen for 15 min, and the reaction was left to stir at room temperature overnight Additional Azido PEG 4  Amine (86.4 mg, 0.3293 mmol) and N,N-Diisopropylethylamine (46.8 mg, 63.1 μL, 0.3622 mmol) were added to the flask, the system was purged with N 2  gas, and the reaction was stirred for 3 h at room temperature. The polymer was precipitated with hexane (˜10× volume), centrifuged, and the solvent was decanted. The polymer was dissolved in minimal dichloromethane, precipitated with hexane (˜10× volume), centrifuged, and the solvent was decanted. The polymer precipitate was dried under high vacuum until the solid reached a constant weight. The yield of Azide functionalized EAP was 1.77 g. Samples of the copolymer were taken for multi-angle light scattering (MALS), and  1 H-NMR.
         Polymer 006: The composition determined by  1 H-NMR was 56% N-Boc-ethoxyethylamine acrylate and 44% propyl acrylate. The Mw determined by MALS was 60,330 g/mol with a polydispersity index (PDI) of 1.05.   Polymer 100A: The composition by H-NMR was 56% N-Boc-ethoxyethylamine acrylate and 44% propyl acrylate. The Mw determined by MALS: 64,430 with PDI of 1.217.   Polymer 064: The composition by 1H-NMR was 54% N-Boc-ethoxyethylamine acrylate and 46% propyl acrylate. The Mw determined by MALS: 65,170 with PDI of 1.05       

     Mono-Azide: The term “mono-azide” or “mono-azide polymer” indicates that steps D and E of the procedures above were done and an azide group was coupled to the α-end group of the polymer. 
     F. Boc Deprotection and Tangential Flow Filtration. In a 100 mL round bottom flask, 2M HCl in acetic acid (28 mL) was added to Azide functionalized EAP copolymer (1.67 g, 0.0277 mmol). The reaction was stirred at room temperature for 1 h. De-ionized H 2 O (56 mL) was added, and stirred for 10 min. The solution was then immediately exchanged with 10 equivalent volumes of 5 mM Phosphate-Citrate buffer (pH 5) using a mPES 30 kD 115 cm 2  filter module equipped with a tangential flow filtration system (KrosFlo Research). The solution was then concentrated using the apparatus to 55 mL final volume. A pH value of 5.1 was recorded. Samples were taken for concentration determination by headspace gas chromatography. An aliquot was lyophilized and then reconstituted in 33.3% Acetonitrile-d in Deuterium Oxide at a concentration of 10 mg/mL for  1 H-NMR analysis. Theoretical MW was calculated to be 43,026 g/mol 45,765 g/mol for 006 and 100A respectively. 
     G. Using similar techniques, similar amphipathic membrane active polyamines can be readily formed. Particularly, amphipathic membrane active polyamines with molecular weight (Mw) 40-120 k protected (25 k to 85 k deprotected), PDI ranges of 1.03 to 1.2, and monomer ratios of 35% amine monomer/65% hydrophobic group monomer to 70% amine monomer/30% hydrophobic group monomer. 
     Example 3. Synthesis of APN 1095-126 (126) 
       
     
       
         
           
               
               
               
               
               
               
               
             
               
                   
               
               
                   
                   
                   
                   
                   
                 % End  
                   
               
               
                 MW 
                 Theoretical MW 
                   
                 % Amine 
                 % Alkyl 
                 Group 
                 Azides Per 
               
               
                 (protected) 
                 (deprotected) 
                 PDI 
                 Incorporation 
                 Incorporation 
                 Removal 
                 Polymer 
               
               
                   
               
             
            
               
                 66,670 
                 47,606 
                 1.11 
                 56 
                 44 
                 0 
                 4.1 
               
               
                   
               
            
           
         
       
     
     Synthesis of APN 1095-126 used dithiobenzoate moiety RAFT agent and AIBN RAFT initiator, compared to the trithiocarbonate moiety RAFT agent and V-65 RAFT initiator used for synthesis of 100A and 006. The conditions for this polymerization required different heating temperatures and times. In addition, this polymer required fractional precipitation. The polymer was not end capped, but the method of azide addition was the same as 100A and 006. 
     A. Materials. Propyl acrylate was purchased from Polysciences Inc. N-Boc-ethoxyethylamine acrylate was obtained from WuXi Inc. 4-Cyano-4-(phenylcarbonothioylthio) pentanoic acid (CPCPA, RAFT Agent), 2,2′-Azobis(2-methylpropionitrile) (AIBN, radical initiator), Pentafluorophenol, N,N′-Dicyclohexylcarbodiimide and N,N-diisopropylethylamine were purchased from Sigma Aldrich. O-(2-Aminoethyl)-O′-(2-azidoethyl)triethylene Glycol (azido-PEG 4 -amine) was purchased from Biomatrik Inc. 
     B. RAFT copolymer of N-Boc-ethoxyethylamine acrylate and propyl acrylate (EAP). The following procedure was repeated 8 times to yield a total of 4.5513 g fractionated EAP copolymer. Solutions of AIBN (1.035 mg/mL) and RAFT agent CPCPA (50.54 mg/mL) in butyl acetate were prepared. Monomer molar feed was 52% N-Boc-ethoxyethylamine acrylate, 48% propyl acrylate. Theoretical Mw was 75,000. RAFT agent (CPCPA) to initiator (AIBN) molar ratio was 6.67:1. 
     N-Boc-ethoxyethylamine acrylate (1.7879 g, 6.9 mmol), propyl acrylate (0.774 mL, 0.7121 g, 6.24 mmol), CPCPA solution (0.184 mL, 0.0333 mmol), AIBN solution (0.793 mL, 0.005 mmol), and butyl acetate (11.02 mL) were added to a 20 mL glass vial with a stir bar. 
     The vial was sealed with a septa cap and the solution bubbled with nitrogen using a long needle with a second needle as the outlet for 1 h. The needles were removed and the vial was heated to 50° C. for 24 h with stirring. The solution was allowed to cool to room temperature and transferred to a 50 mL centrifuge tube before hexane (35 mL) was added. The solution was centrifuged for 2 min at 4400 rpm. The supernatant layer was carefully decanted and the bottom layer rinsed with hexane. The bottom layer of each tube was then re-dissolved in dichloromethane (7 mL), precipitated in hexane (40 mL) and centrifuged once more. The supernatant was decanted and the bottom layer rinsed with Hexane before the polymer was dried under reduced pressure for several hours. The yield of crude EAP copolymer was 1.734 g. Samples of the crude copolymer were taken for multi-angle light scattering (MALS), and  1 H-NMR. The dried, crude copolymer was dissolved in DCM (100 mg/mL). Hexane was added until just after the cloud point was reached. The resulting milky solution was centrifuged. The bottom layer was extracted and fully precipitated into hexane. The fraction was centrifuged, after which the copolymer was isolated and dried under vacuum. The yield of isolated fraction of EAP copolymer was 0.602 g. Samples of the fractionated copolymer were taken for  1 H-NMR and MALS. The composition determined by  1 H-NMR was 56% N-Boc-ethoxyethylamine acrylate and 44% propyl acrylate. The Mw determined by MALS was 62,010 g/mol with a polydispersity index (PDI) of 1.14. 
     C. Pentafluorophenol activation of α-end group. EAP polymer (2 g, 0.0347 mmol), pentafluorophenol (63.8 mg, 0.3466 mmol), N,N′-Dicyclohexylcarbodiimide (71.5 mg, 0.3466 mmol), and dichloromethane (40 mL) were added to a 100 mL round bottom flask with a stir bar. The flask was stoppered with a rubber septum and the system was purged with nitrogen for 15 min. The solution was stirred for 16 h at room temperature. Additional Pentafluorophenol (63.8 mg, 0.3466 mmol) and N,N′-Dicyclohexylcarbodiimide (71.5 mg, 0.3466 mmol) were added, the flask stoppered with a rubber septum, and the system was purged with nitrogen for 15 min. The solution was stirred for 3 h at room temperature. The polymer was precipitated with hexane (˜10× volume), centrifuged, and the solvent was decanted. The polymer was dissolved in minimal dichloromethane, precipitated with hexane (˜10× volume), centrifuged, and the solvent was decanted. The polymer was dissolved in minimal ethyl acetate, precipitated with hexane (˜10× volume), centrifuged, and the solvent was decanted. The polymer precipitate was dried under high vacuum until the solid reached a constant weight. 
     D. Azide functionalization of α-end group. In a 100 ml round bottom flask equipped with a rubber septum and stir bar, polymer from the previous step (1.9 g, 0.0329 mmol) was dissolved in dichloromethane (38 mL). Azido-PEG 4 -Amine (86.4 mg, 0.3293 mmol) and N,N-Diisopropyl-ethylamine (46.8 mg, 63.1 μL, 0.3622 mmol) were added to the flask with stirring. 
     The system was purged with nitrogen for 15 min, and the reaction was left to stir at room temperature overnight. Additional Azido PEG 4  Amine (86.4 mg, 0.3293 mmol) and N,N-Diisopropyl-ethylamine (46.8 mg, 63.1 μL, 0.3622 mmol) were added to the flask, the system was purged with N 2  gas, and the reaction was stirred for 3 h at room temperature. The polymer was precipitated with hexane (˜10× volume), centrifuged, and the solvent was decanted. The polymer was dissolved in minimal dichloromethane, precipitated with hexane (˜10× volume), centrifuged, and the solvent was decanted. The polymer precipitate was dried under high vacuum until the solid reached a constant weight. The yield of Azide functionalized EAP was 1.77 g. Samples of the copolymer were taken for multi-angle light scattering (MALS), and  1 H-NMR. The composition determined by  1 H-NMR was 56% N-Boc-ethoxyethylamine acrylate and 44% propyl acrylate. The Mw determined by MALS was 66,670 g/mol with a polydispersity index (PDI) of 1.11. 
     E. Boc Deprotection and Tangential Flow Filtration. In a 100 mL round bottom flask, 2M HCl in acetic acid (28 mL) was added to Azide functionalized EAP copolymer (1.67 g, 0.0277 mmol). The reaction was stirred at room temperature for 1 hour. De-ionized H 2 O (56 mL) was added, and stirred for 10 min. The solution was then immediately exchanged with 10 equivalent volumes of 5 mM Phosphate-Citrate buffer (pH 5) using a mPES 30 kD 115 cm 2  filter module equipped with a tangential flow filtration system (KrosFlo Research). The solution was then concentrated using the apparatus to 55 mL final volume. A pH value of 5.1 was recorded. Samples were taken for concentration determination by headspace gas chromatography. An aliquot was lyophilized and then reconstituted in 33.3% Acetonitrile-d in Deuterium Oxide at a concentration of 10 mg/mL for  1 H-NMR analysis. Theoretical MW was calculated to be 43,026 g/mol. 
     Example 4. Polymer Analytics 
     
         
         
           
             (i) MALS analysis. Approximately 10 mg of the copolymer was dissolved in 0.5 mL 75% dichloromethane, 20% tetrahydrofiran, and 5% acetonitrile. The molecular weight and polydispersity (PDI) were measured using a Wyatt Heleos II multiangle light scattering detector attached to a Shimadzu Prominence HPLC using a Jordi 5 μm 7.8×300 Mixed Bed LS DVB column. Molecular weight (polymer 006) before de-protection: 60,330 (PDI 1.05). 
             (ii) Monomer conversion by Gas Chromatography. Approximately 40 μL of copolymer solution (section B) was taken after mixing (pre-N 2  bubbling), after N 2  bubbling, and after reaction completion. Samples were diluted 100 fold into ethyl acetate. The samples were analyzed with a Shimadzu GC-2010 plus equipped with a flame ionization detector using a Phenomenex Zebron capillary column (ZB-5, 30 m, 0.25 mm ID, 0.5 μm film thickness). Using the pre-N 2  bubbled sample as a single point calibration, monomer conversion was measured by comparing post reaction monomer concentrations with pre reaction/post N 2  bubbling monomer concentrations. 
             (iii) Polymer concentration by propanol content using headspace gas chromatography (HS-GC). Deprotected polymer solution (˜20 mg/mL) was diluted 50 fold into 3M NaOH using 1-Butanol as an internal standard. The reaction tube was sealed and shaken for 1 h. The reaction was then incubated for at least 6 h at room temperature. In a 10 mL headspace vial, hydrolyzed test article (250 μL) was added to saturated NaCl (500 μL) and HCl (4M, 250 μL) and the system was sealed. Test articles were analyzed using a Shimadzu GC-2010 plus with HS-20 headspace sampler using a Phenomenex ZB-WAX plus gc column (30.0 m, 0.25 mm ID, 0.25 μm film thickness). Propanol concentration was then quantitated using an external standard curve or propanol containing the same NaCl/HCl/NaOH matrix. Polymer concentration was then calculated by dividing propanol concentration by the amount of propanol per polymer as determined by monomer incorporation. 
             (iv) Azide quantitation using UV Spectroscopy. Deprotected polymer solution (˜20 mg/mL) was diluted to −5 mg/mL in 60 mM MES, pH 6. The polymer was then reacted with DBCO-amine (2.5 molar eq.) at room temperature for at least 6 h. The difference in absorbance at 310 nm was calculated and azide content per polymer was determined. 
           
         
       
    
     Example 5. Tangential Flow Filtration and Analysis of Conjugate 
     Following Conjugate formation, i.e., modification of polymer by addition of RGD and PEG modifying agents and attachment of RNAi trigger (see example 9 below) the conjugate solution (2 mg/mL, 10 mL) was exchanged with 10 equivalent volumes of 10 mM Phosphate-Citrate buffer (pH 5) using a mPES 30 kD 20 cm 2  filter module equipped with a tangential flow filtration system (KrosFlo Research). A pH value of 5.1 was recorded. 
     A. Conjugate characterization and analysis.
         (i) Polymer Concentration Throughout Conjugation. The Same Method as Section G(iii) was used throughout the assembly of the conjugate to monitor polymer concentration.   (ii) Impurity quantitation by HPLC-reverse-phase chromatography. Polymer conjugate (after TFF purification) was diluted to 1 mg/mL with H 2 O and injected onto a Shimadzu Prominence HPLC with a SPD-20A UV detector and a Waters Xbridge C18 5 μm 4.6×250 mm column. The method used a binary gradient consisting of H 2 O/Acetonitrile/0.1% formic acid with detection set to 247 nm. Concentrations of PEG n -ACit-PABOH, RGD-PEG n -FCFP-COOH, and PNP were calculated using external standard quantitation.   (iii) RGD-PEG n -FCitFP-TFP and PEG n -ACit-PABC-PNP modification through amino acid analysis. Polymer conjugate (after TFF purification) with NorValine as an internal standard was hydrolyzed for 16 h in HCl (6 M) at 110° C. in a sealed hydrolysis tube. The hydrolysis solution was then neutralized with NaOH, diluted with borate buffer (pH 10.1), and derivatized with phthaldialdehyde/3-mercaptopropionic acid. The sample was then injected onto a Shimadzu Nexera HPLC system with SIL-30A autosampler, SPD-20A photo diode array detector, and a Waters Xbridge C18 5 μm 4.6×250 mm column. Sample was eluted using a 10 mM Sodium tetraborate decahydrate/10 mM dibasic sodium phosphate/5 mM Sodium azide and 45% Methanol/45% Acetonitrile/10% H 2 O binary gradient. UV detection was set to 338 nm. Alanine and Phenylalanine concentrations were calculated using external standard curves. Alanine and Phenylalanine concentrations along with polymer concentration and monomer incorporations were used to calculate total amine group modification, as well as the ratio between both ligands.   (iv) RNA trigger quantitation and conjugate purity by size exclusion chromatography. A Shimadzu Prominence HPLC equipped with SPD-20A UV detector and Acclaim SEC-300 4.6 mm×300 mm, 5 μm, 300 Å size exclusion column (11 st  in series) connected to Acclaim SEC-1000 4.6 mm×300 mm, 7 μm, 1000 Å (2 nd  in series) size exclusion column was assembled. The method used was isocratic, with 200 mM NaBr, 10 mM Tris pH 8, 1 mM EDTA, and 20% Acetonitrile as mobile phase and detection at 260 nm. A sample of polymer conjugate (after RNA trigger addition) was diluted into mobile phase and injected onto the system. Another sample of conjugate followed the same dilution scheme but was treated with 200 mM dithiothreitol for 2 h before injection onto the system. RNA trigger concentration for both samples was calculated using an external standard curve. Amount of conjugated RNA trigger was calculated by subtracting DTT treated RNA levels from untreated RNA levels. Post-TFF purity of the conjugate was also determined using this method.       

     Example 6. RGD Ligands (RGD Mimic) 
     
       
         
         
             
             
         
       
     
     A. RGD mimic #1-PEG n -HyNic, MW 1272. 
     
       
         
         
             
             
         
       
         
         
           
             n=4-24 (preferably 8-12) PGP 
           
         
       
    
     B. RGD mimic #1a-HyNic, MW 802.8. 
     
       
         
         
             
             
         
       
     
     C. RGD mimic #1b-HyNic, MW 830.9 (RGD). 
     
       
         
         
             
             
         
       
     
     Example 7. RGD and PEG Modifying Agents 
     A. Dipeptide RGD-dipeptide and PEG-dipeptide modifying agents were made as described in US-2012-0172412-A1 (WO 2012/092373) and US 2015-0045573 A1 (WO 2015/021092) (both of which are incorporated herein by reference).  FIG. 3-7 . 
     B. RGD-PEG n -FCitFP-TFP and PEG n -FCitFP-TFP modifying agent synthesis. The modifying agent precursor (di-Boc)RGD(OtBu)-APBA-PEG n -FCitFPro-COOH was prepared using general Fmoc chemistry solid phase synthesis using 2-Cl-Trt resin preloaded with Fmoc-Proline-OH. To Resin-Pro-Fmoc was added sequentially (following Fmoc deprotection at each step): FMoc-Phe-OH, Fmoc-Cit-OH, Fmoc-Phe-OH, Fmoc-NH-PEG n -COOH, 4-(N-Fmoc-p-aminophenoxy)-butyric acid (APBA), Fmoc-Asp(OtBu)-OH, Fmoc-Gly-OH, and diboc-m-guanidino benzoic acid. 
     (diboc)RGD(OtBu)-APBA-PEG n -FCitFPro-COOH (458 mg, 0.200 mmols) and TFP (66.5 mg, 0.400 mmols) were dissolved in anhydrous DCM (5.0 mL) and cooled to 0° C. in an ice/water bath while stirring under Argon. EDC (77 mg, 0.400 mmols) was added and the reaction mixture stirred in an ice/water bath at 0° C. for 30 min. Reaction progress was monitored by TLC (8.5:1.5 CHCl 3 :MeOH) and was complete after 90 min with no starting material observed by TLC. The reaction mixture was diluted to 100 mL total volume with DCM, washed 3×40 mL with DI H 2 O (pH=5), and washed 1×40 mL aqueous saturated NaCl solution. The organics were then dried over Na 2 SO 4 , and concentrated on a rotovap to yield 448 mg (92% yield) of a tan/orange foam. The structure was confirmed by  1 H NMR, and ESI MS (Reaction shown above for PEG 20  (n=20)). 
     
       
         
         
             
             
         
       
         
         
           
             (diboc)RGD(OtBu)-APBA-PEG n -FCitFPro-TFP
           (shown for n=20)   
         
           
         
       
    
     (diboc)RGD(OtBu)-PEG n -FCitFPro-TFP (497 mg, 0.204 mmols) was dissolved in [9.25:0.75:0.50] TFA:H 2 O:Thioanisole (5.0 mL) and stirred at room temperature in a closed flask for 45 min. Reaction completion was confirmed by MS (ESI, scan neg, 300-3000) with no masses related to starting material or partially deprotected intermediates observed. The reaction mixture was then precipitated into 45 mL diethyl ether, spun down, the supernatant poured off, and washed 2×10 mL diethyl ether and dried on high vacuum overnight. The final product was purified on prep HPLC using a Thermo Aquasil C18 5 μm semi prep column, with mobile phases 0.1% TFA in H 2 O and ACN. Each injection was 50 mg of crude material dissolved in 3.0 mL of 0.1% TFA in [61:39] H 2 O:ACN run on a gradient of (indicated in % B) 39-(5)-39-(35)-43-(5)-95-(10)-95-(2)-39-(5)-39. Each sample for injection was prepared (dissolved) within 15 minutes of being injected and positive fractions were pooled in one flask and kept cold in the freezer until the last injection of the day had finished. The positive fractions were then concentrated on the rotovap with a bath temperature of 32° C. to dryness, then chased 2× with ACN/Toluene, then 3× with ACN and then dried on high vacuum overnight. Out of 257 mg injected crude, 180 mg (70%) was isolated as pure material (Reaction shown above for PEG 20  (n=20)). 
     
       
         
         
             
             
         
       
         
         
           
             RGD-PEG n -FCitFPro-TFP
           (shown for n=20)   
         
           
         
       
    
     4-(N-Fmoc-p-aminophenoxy)-butyric acid 1 synthesis. p-Nitro-phenol (2) (7.5 g, 53.9 mmole) was combined with ethyl 4-bromobutyrate (8.45 ml, 59 mmol) and K 2 CO 3  (7.5 g, 54 mmole) in DMF (75 mL). The mixture was stirred for 2 h at 100° C. DMF was removed and the crude product was diluted in a mixture of 3:1 mixture of 2 N NaOH and methanol and stirred 4 h at RT. The reaction mixture was acidified with 6 M HCl. The white precipitate was collected to yield 4-(p-Nitrophenyloxy)-butyric acid 3: (10.9 g, 90% yield). 4-(p-Nitrophenyloxy)-butyric acid 3 (37.1 g, 165 mmole) was dissolved in MeOH (1 L) with ammonium formate (35 g, 555 mmole) and 10% Pd/C (Degussa Type) (3.5 g) was added. The mixture was refluxed at 65° C. overnight. The reaction was filtered with celite to yield a reddish brown solid of product 4-(p-Aminophenyloxy)-butyric acid 4 (30.5 g, 95% yield). 
     4-(p-Aminophenyloxy)-butyric acid 4 (5.1 g, 26 mmole) was dissolved in 6:4 a mixture of an aqueous saturated NaHCO 3 (3.36 g, 40 mmol) in H 2 O (450 mL) and THF (300 ml) to make a white slurry. Fmoc-OSu (8.82 g, 26.1 mmole) was added and the reaction was stirred for 4 h. The acetone was removed, the reaction was acidified (HCl), and the off-white precipitate was collected and triturated in 1N HCl to yield 9.6 g of product 4-(N-Fmoc-p-aminophenoxy)-butyric acid 1 (88% yield). 
     
       
         
         
             
             
         
       
         
         
           
             diBoc-m-guanidino-benzoic acid 5 was synthesized according to Riches A G et al. Tetrahedron (2012) 68, p. 9448-9455. 
           
         
       
    
     PEGe-FCitFP modifying agents were made using similar chemistry.  FIG. 1-2 . 
     Example 8. Tetrapeptide Peptide Linkages 
     A. Tetrapeptide Syntheses. All tetrapeptides were synthesized in the same manner using standard solid phase Fmoc procedures. Some peptides were synthesized from commercially available 2-Cl-Trt resin (EMD Millipore, Billerica, Mass.) containing either proline, leucine, or alanine. For other peptides, 2-Cl-Trt resin was loaded with either FMOC-PEG n -CO 2 H or FMOC-N-methyl-Ala-CO 2 H by adding a solution of DMF containing the amino acid or PEG (1 eq) and DIEA (2 eq) to 2-Cl-Trt resin for 16 h. Upon completion, resins were capped with MeOH. Stepwise addition was performed using PYBOP (4 eq), amino acid (4 eq), and DIEA (8 eq) for coupling and 20% piperdine in DMF for Fmoc de-protection. 
     After peptide syntheses, the tetrapeptides were reacted with 2 eq of N-Hydroxysuccinimide (NHS) activated esters of either protected N-Acetyl-galactosamine, NAG(OAc) 3  (Rozema D B et al. “Protease-triggered siRNA Delivery Vehicles.” J Control Release. 2015 Vol. 209:57-66 and U.S. Pat. No. 8,802,773) or PEG n  in DMF containing 4 eq DIEA. Following attachment of NAG(OAc) 3  or PEG, the peptides were removed from resin using HFIP (30%) in DCM for 0.5 h. After solvent removal the residue was triturated with Et 2 O. 
     Tetrapeptides were either purified and conjugated to activated esters to form modifying agents or conjugated to chromophore N-(p-Nitrophenyl)ethylenediamine (pNA) without purification to form substrates for physiological lability testing. Prior to purification, NAG(OAc) 3 -containing substrates were de-acetylated by treatment with TEA (35%) in water (45%) and MeOH (20%) and stirred at room temp. For purification, tetrapeptide substrates were separated by HPLC using a Thermo Scientific Aquasil C18 reverse-phase column (250×21.2, Waltham, Mass.), eluting a gradient of acetonitrile and water buffered with 0.1% formic acid. Following purification, the substrates were lyophilized. 
     Attachment of amine-reactive groups to tetrapeptides. 1 eq HPLC purified peptide with N-terminal NAG (RS=NAG(OH) 3  or PEG (R=PEGe) in DMF or DCM was added to a flame dried flask at 0° C. to give a 0.2 M concentration of peptide. NHS (3 eq) and N,N′-Dicyclohexylcarbodiimide (DCC) (3 eq) were added and allowed to stir at room temp. under argon overnight to yield the modifying agents. The mixture was partially concentrated, chilled to −20° C., and filtered. All solvents were then removed in vacuo. The residue was dissolved in a minimum of DCM and MeOH, precipitated into cold Et 2 O and collected by decantation of the solvent after centrifugation. Precipitation into Et 2 O was repeated until no residual DCU (dicyclohexylurea) was detectable. All prepared compounds were subsequently used without further purification. 
     Example 9. Polymer Modification 
     Formation of siRNA delivery conjugate using RGD-PEG-HyNic, RGD-PEG-ACit-PNP, or RDG-PEG-FCitFP-TFP and PEG-dipeptide modifying agents. 
     1) Protocol 1. The indicated polymer was reacted with SMPT at a weight ratio of 1:0.015 (polymer:SMPT) in 5 mM HEPES, pH 8.0 buffer for 1 h at RT. The SMPT-modified polymer was then reacted with aldehyde-PEG-dipeptide modifying agent (aldehyde-PEG 12 -FCit or aldehyde-PEG 24 -ACit) at desired ratios for 1 h at RT. The modified polymer was then reacted with PEG 12 -dipeptide modifying agent (PEG 12 -FCit, PEG 12 -ACit or PEG 24 -ACit) at a weight ratio of 1:2 (polymer:PEG) in 100 mM HEPES, pH 9.0 buffer for 1 h at RT. The modified polymer was then reacted overnight with SATA-RNAi trigger at a weight ratio of 1:0.2 (polymer:SATA-RNAi trigger) in 100 mM HEPES, pH 9.0 buffer at RT to attach the RNAi trigger. Next, the modified polymer was reacted with protease cleavable PEG (PEG 12 -FCit or PEG 12 -ACit or PEG 24 -ACit) at a weight ratio of 1:6 (polymer:PEG) in 100 mM HEPES, pH 9.0 buffer for 1 h at RT. The resultant conjugate was purified using a sephadex G-50 spin column.
         RGD-HyNic (Example 6B) was attached to the modified polymer to form the full delivery conjugate by reaction with the modified polymer at a weight ratio of 1:0.7 (polymer:RGD-HyNic mimic) in 50 mM MES, pH 5.0 buffer for a minimum of 4 h at RT. The conjugate was purified using a sephadex G-50 spin column. RGD ligand attachment efficiency was determined as described above.       

     2) Protocol 2. The indicated polymer was reacted with SMPT at a weight ratio of 1:0.015 (polymer:SMPT) in 5 mM HEPES, pH 8.0 buffer for 1 h at RT. The SMPT-modified polymer was then reacted with aldehyde-PEG-dipeptide modifying agent (aldehyde-PEG 24 -ACit) at a weight ratio of 1:0.5 (polymer:PEG) and with PEG-dipeptide modifying agent (PEG 12 -FCit, PEG 12 -ACit or PEG 24 -ACit) at a weight ratio of 1:2 (polymer:PEG) in 100 mM HEPES, pH 9.0 buffer for 1 h at RT. The modified polymer was then reacted overnight with SATA-RNAi trigger at a weight ratio of 1:0.2 (polymer:SATA-RNAi trigger) in 100 mM HEPES, pH 9.0 buffer at RT to attach the RNAi trigger. Next, the modified polymer was reacted with protease cleavable-PEG (PEG 12 -FCit or PEG 12 -ACit or PEG 24 -ACit) at a weight ratio of 1:6 (polymer:PEG) in 100 mM HEPES, pH 9.0 buffer for 1 h at RT. RGD-HyNic (Example 6) was attached to the modified polymer to form the full conjugate by reaction with the modified polymer at a weight ratio of 1:0.7 (polymer:RGD-HyNic) in 69 mM hydrogen chloride solution (HCl) overnight at RT. RGD ligand attachment efficiency was determined as described above. 3) Protocol 3. The indicated polymer was reacted with SMPT at a weight ratio of 1:0.015 (polymer:SMPT) in 5 mM HEPES, pH 8.0 buffer for 1 h at RT. The SMPT-modified polymer was then reacted with aldehyde-PEG-dipeptide modifying agent (aldehyde-PEG 24 -ACit) at a weight ratio of 1:0.5 (polymer:PEG) and with PEG-dipeptide modifying agent (PEG 12 -FCit, PEG 12 -ACit or PEG 24 -ACit) at a weight ratio of 1:2 (polymer:PEG) in 50 mM HEPES, pH 9.0 buffer for 1 h at RT. The modified polymer was then reacted overnight with SATA-RNAi trigger at a weight ratio of 1:0.2 (polymer:SATA-RNAi trigger) in 50 mM HEPES, pH 9.0 buffer at RT to attach the RNAi trigger. Next, the modified polymer was reacted with protease cleavable-PEG (PEG 12 -FCit or PEG 12 -ACit or PEG 24 -ACit) at a weight ratio of 1:6 (polymer:PEG) in 50 mM HEPES, pH 9.0 buffer for 1 h at RT. RGD-HyNic (Example 6) was attached to the modified polymer to form the full delivery conjugate by reaction with the modified polymer at a weight ratio of 1:0.7 (polymer:RGD-HyNic mimic) in 100 mM MES free acid solution overnight at RT. RGD targeting ligand conjugation efficiency was determined as described above. 
     4) Protocol 4. The indicated polymer was reacted with Azido-PEG 4 -NHS at a weight ratio of 1:0.015 (polymer:Azido) in 5 mM HEPES, pH 8.0 buffer for 1 h at RT. The Azido-modified polymer was then reacted with aldehyde-PEG-dipeptide modifying agent (aldehyde-PEG 24 -ACit) at a weight ratio of 1:0.5 (polymer:PEG) and with PEG-dipeptide modifying agent (PEG 12 -ACit) at a weight ratio of 1:2 (polymer:PEG) in 50 mM HEPES, pH 9.0 buffer for 1 h at RT. The modified polymer was then reacted overnight with Alkyne-RNAi trigger at a weight ratio of 1:0.2 (polymer:Alkyne-RNAi trigger) in 50 mM HEPES, pH 9.0 buffer at RT to attach the RNAi trigger. Next, the modified polymer was reacted with protease cleavable-PEG (PEG 12 -ACit) at a weight ratio of 1:6 (polymer:PEG) in 50 mM HEPES, pH 9.0 buffer for 1 h at RT. RGD-HyNic (Example 6) was attached to the modified polymer to form the full delivery conjugate by reaction with the modified polymer at a weight ratio of 1:0.7 (polymer:RGD-HyNic mimic) in 100 mM sodium acetate-acetic acid buffer solution, pH 5.0 overnight at RT. RGD targeting ligand conjugation efficiency was determined as described above. 
     5) Protocol S. The mono azide-polymer was reacted with aldehyde-PEG-dipeptide modifying agent (aldehyde-PEG 24 -ACit) at a weight ratio of 1:0.5 (polymer:PEG) and with PEG-dipeptide modifying agent (PEG 12 -ACit) at a weight ratio of 1:2 (polymer:PEG) in 50 mM HEPES, pH 9.0 buffer for 1 h at RT. The modified polymer was then reacted overnight with Alkyne-RNAi trigger at a weight ratio of 1:0.2 (polymer:Alkyne-RNAi trigger) in 50 mM HEPES, pH 9.0 buffer at RT to attach the RNAi trigger. Next, the modified polymer was reacted with protease cleavable-PEG (PEG 12 -ACit) at a weight ratio of 1:6 (polymer:PEG) in 50 mM HEPES, pH 9.0 buffer for 1 h at RT. RGD-HyNic (Example 6) was attached to the modified polymer to form the full delivery conjugate by reaction with the modified polymer at a weight ratio of 1:0.7 (polymer:RGD-HyNic mimic) in 100 mM sodium acetate-acetic acid buffer solution, pH 5.0 overnight at RT. RGD targeting ligand conjugation efficiency was determined as described above. 
     6) Protocol 6. The mono azide-polymer was reacted with protease cleavable-RGD agent (RGD-PEG 8 -ACit-PNP, RDG-PEG 8 -FCitFP-TFP, RGD-PEG 15 -FCitFP-TFP, RGD-PEG 19 -FCitFP-TFP, or RGD-PEG 20 -FCitFP-TFP) at weight ratios of 1:0.125, 1:0.25, 1:0.5, 1:1, 1:1.5, 1:2 (polymer:RGD) in 50 mM HEPES, pH 8.5 buffer for 4 h at RT. The modified polymer was then reacted with protease cleavable-PEG agent (PEG 6 -ACit-PABC-PNP, PEG 12 -ACit-PABC-PNP, PEG 12 -FCit-PABC-PNP, PEG 12 -FCitFP-TFP) at a weight ratio of 1:8 (polymer:PEG) in 50 mM HEPES, pH 8.5 buffer for 2 h at RT. Alkyne-RNAi trigger at a weight ratio of 1:0.3 (polymer:Alkyne-RNAi trigger) was added to the modified polymer in 100 mM sodium acetate-acetic acid buffer solution, pH 5.0 for 5 days at RT. The completed conjugate was TFF purified and conjugation efficiency determined. 
     7) Protocol 7. The mono azide-polymer was reacted with protease cleavable-RGD agent (RGD-PEG 20 -FCitFP-TFP) at weight ratio of 1:1 (polymer:RGD) in 50 mM HEPES, pH 8.5 buffer for 2 h at RT. The modified polymer was then reacted with protease cleavable-PEG agent (PEG 12 -ACit-PABC-PNP) at a weight ratio of 1:8 (polymer:PEG) in 50 mM HEPES, pH 8.5 buffer for 2 h at RT. The modified polymer was then TFF purified. Alkyne-RNAi trigger at a weight ratio of 1:0.4 (polymer:Alkyne-RNAi trigger) was added to the TFF purified polymer for 3 days at 37° C. 
     Example 10. In Vitro Analysis of Hf2α RNAi Triggers 
     Candidate sequences were identified by in silico analysis and screened as chemically modified canonical siRNAs in vitro. For screening purposes, the human EPAS1 (Hif2a) cDNA sequence (accession #NM_001430) was synthesized and cloned (DNA 2.0, Menlo Park, Calif.) into a commercially-available reporter-based screening plasmid, psiCHECK2 (Promega, Madison, Wis.) which generated a  Renilla  luciferase/EPAS1 fusion mRNA. For RNAi trigger efficacy evaluation, Hep3B cells, a human hepatocellular carcinoma line, were plated at ˜10,000 cells per well in 96-well format. Each of the 187 EPAS1 RNAi triggers, in two subsets, was co-transfected at two concentrations, 1 nM and 0.1 nM, with 25 ng EPAS1-psiCHECK2 plasmid DNA per well and 0.2 μL LipoFectamine 2000 (Life Technologies) per well. Gene knockdown was determined by measuring  Renilla  luciferase levels normalized to the levels of constitutively-expressed firefly luciferase, also present on the psiCHECK-2 plasmid, using the Dual Luciferase Reporter Assay (Promega, Madison, Wis.) Table 5. 
     
       
         
           
               
             
               
                 TABLE 5A 
               
             
            
               
                   
               
               
                 Unmodified Hif2α RNAi trigger antisense  
               
               
                 strand and sense strand sequences. 
               
            
           
           
               
               
               
               
            
               
                 SEQ 
                   
                 SEQ 
                   
               
               
                 ID 
                 Sense Strand 
                 ID 
                 Antisense Strand 
               
               
                 NO. 
                 Sequence (5′ → 3′) 
                 NO. 
                 Sequence (5′ → 3′) 
               
               
                   
               
               
                 285 
                 GAGACUGUAUGGUCAGCUC 
                 478 
                 GAGCUGACCAUACAGUCUC 
               
               
                   
               
               
                 286 
                 CUCCGACUCCUUCCGACUC 
                 479 
                 GAGUCGGAAGGAGUCGGAG 
               
               
                   
               
               
                 287 
                 UCCGACUCCCAGCAUUCGA 
                 480 
                 UCGAAUGCUGGGAGUCGGA 
               
               
                   
               
               
                 288 
                 CGACUCCCAGCAUUCGAGC 
                 481 
                 GCUCGAAUGCUGGGAGUCG 
               
               
                   
               
               
                 289 
                 GACUCCCAGCAUUCGAGCC 
                 482 
                 GGCUCGAAUGCUGGGAGUC 
               
               
                   
               
               
                 290 
                 CAGGUGCUCGGCGUCUGAA 
                 483 
                 UUCAGACGCCGAGCACCUG 
               
               
                   
               
               
                 291 
                 GUGCUCGGCGUCUGAACGU 
                 484 
                 ACGUUCAGACGCCGAGCAC 
               
               
                   
               
               
                 292 
                 UCGGCGUCUGAACGUCUCA 
                 485 
                 UGAGACGUUCAGACGCCGA 
               
               
                   
               
               
                 293 
                 GGCGUCUGAACGUCUCAAA 
                 486 
                 UUUGAGACGUUCAGACGCC 
               
               
                   
               
               
                 294 
                 CGUCUGAACGUCUCAAAGG 
                 487 
                 CCUUUGAGACGUUCAGACG 
               
               
                   
               
               
                 295 
                 AAAAGGAGUAGCUCGGAGA 
                 488 
                 UCUCCGAGCUACUCCUUUU 
               
               
                   
               
               
                 296 
                 GGGUUUCAUUGCCGUGGUG 
                 489 
                 CACCACGGCAAUGAAACCC 
               
               
                   
               
               
                 297 
                 UUCAUGGGACUUACACAGG 
                 490 
                 CCUGUGUAAGUCCCAUGAA 
               
               
                   
               
               
                 298 
                 GGGACUUACACAGGUGGAG 
                 491 
                 CUCCACCUGUGUAAGUCCC 
               
               
                   
               
               
                 299 
                 ACACAGGUGGAGCUAACAG 
                 492 
                 CUGUUAGCUCCACCUGUGU 
               
               
                   
               
               
                 300 
                 GAGCUAACAGGACAUAGUA 
                 493 
                 UACUAUGUCCUGUUAGCUC 
               
               
                   
               
               
                 301 
                 GCUAACAGGACAUAGUAUC 
                 494 
                 GAUACUAUGUCCUGUUAGC 
               
               
                   
               
               
                 302 
                 CUAACAGGACAUAGUAUCU 
                 495 
                 AGAUACUAUGUCCUGUUAG 
               
               
                   
               
               
                 303 
                 GGACAUAGUAUCUUUGACU 
                 496 
                 AGUCAAAGAUACUAUGUCC 
               
               
                   
               
               
                 304 
                 UCUUUGACUUCACUCAUCC 
                 497 
                 GGAUGAGUGAAGUCAAAGA 
               
               
                   
               
               
                 305 
                 UCACUCAUCCCUGCGACCA 
                 498 
                 UGGUCGCAGGGAUGAGUGA 
               
               
                   
               
               
                 306 
                 GAGAUUCGUGAGAACCUGA 
                 499 
                 UCAGGUUCUCACGAAUCUC 
               
               
                   
               
               
                 307 
                 UUCGUGAGAACCUGAGUCU 
                 500 
                 AGACUCAGGUUCUCACGAA 
               
               
                   
               
               
                 308 
                 UCGUGAGAACCUGAGUCUC 
                 501 
                 GAGACUCAGGUUCUCACGA 
               
               
                   
               
               
                 309 
                 GACAUGUCCACAGAGCGGG 
                 502 
                 CCCGCUCUGUGGACAUGUC 
               
               
                   
               
               
                 310 
                 GCGGGACUUCUUCAUGAGG 
                 503 
                 CCUCAUGAAGAAGUCCCGC 
               
               
                   
               
               
                 311 
                 GGAUGAAGUGCACGGUCAC 
                 504 
                 GUGACCGUGCACUUCAUCC 
               
               
                   
               
               
                 312 
                 CACGGUCACCAACAGAGGC 
                 505 
                 GCCUCUGUUGGUGACCGUG 
               
               
                   
               
               
                 313 
                 UCACCAACAGAGGCCGUAC 
                 506 
                 GUACGGCCUCUGUUGGUGA 
               
               
                   
               
               
                 314 
                 CACCAACAGAGGCCGUACU 
                 507 
                 AGUACGGCCUCUGUUGGUG 
               
               
                   
               
               
                 315 
                 AGGCCGUACUGUCAACCUC 
                 508 
                 GAGGUUGACAGUACGGCCU 
               
               
                   
               
               
                 316 
                 UCCUCACAAUAGUCUGUGU 
                 509 
                 ACACAGACUAUUGUGAGGA 
               
               
                   
               
               
                 317 
                 AAUAGUCUGUGUGGCUACA 
                 510 
                 UGUAGCCACACAGACUAUU 
               
               
                   
               
               
                 318 
                 CAGAACUGAUUGGUUACCA 
                 511 
                 UGGUAACCAAUCAGUUCUG 
               
               
                   
               
               
                 319 
                 AGAACUGAUUGGUUACCAC 
                 512 
                 GUGGUAACCAAUCAGUUCU 
               
               
                   
               
               
                 320 
                 CUGAUUGGUUACCACCCUG 
                 513 
                 CAGGGUGGUAACCAAUCAG 
               
               
                   
               
               
                 321 
                 UUGGCCGCUCAGCCUAUGA 
                 514 
                 UCAUAGGCUGAGCGGCCAA 
               
               
                   
               
               
                 322 
                 UAUGAAUUCUACCAUGCGC 
                 515 
                 GCGCAUGGUAGAAUUCAUA 
               
               
                   
               
               
                 323 
                 AUGAAUUCUACCAUGCGCU 
                 516 
                 AGCGCAUGGUAGAAUUCAU 
               
               
                   
               
               
                 324 
                 UGAAUUCUACCAUGCGCUA 
                 517 
                 UAGCGCAUGGUAGAAUUCA 
               
               
                   
               
               
                 325 
                 GAAUUCUACCAUGCGCUAG 
                 518 
                 CUAGCGCAUGGUAGAAUUC 
               
               
                   
               
               
                 326 
                 AAUUCUACCAUGCGCUAGA 
                 519 
                 UCUAGCGCAUGGUAGAAUU 
               
               
                   
               
               
                 327 
                 UCUACCAUGCGCUAGACUC 
                 520 
                 GAGUCUAGCGCAUGGUAGA 
               
               
                   
               
               
                 328 
                 AUGCGCUAGACUCCGAGAA 
                 521 
                 UUCUCGGAGUCUAGCGCAU 
               
               
                   
               
               
                 329 
                 UGCGCUAGACUCCGAGAAC 
                 522 
                 GUUCUCGGAGUCUAGCGCA 
               
               
                   
               
               
                 330 
                 GUAAGUGGCCAGUACCGGA 
                 523 
                 UCCGGUACUGGCCACUUAC 
               
               
                   
               
               
                 331 
                 UAAGUGGCCAGUACCGGAU 
                 524 
                 AUCCGGUACUGGCCACUUA 
               
               
                   
               
               
                 332 
                 CCAGUACCGGAUGCUCGCA 
                 525 
                 UGCGAGCAUCCGGUACUGG 
               
               
                   
               
               
                 333 
                 AGUACCGGAUGCUCGCAAA 
                 526 
                 UUUGCGAGCAUCCGGUACU 
               
               
                   
               
               
                 334 
                 UACCGGAUGCUCGCAAAGC 
                 527 
                 GCUUUGCGAGCAUCCGGUA 
               
               
                   
               
               
                 335 
                 UGCUCGCAAAGCAUGGGGG 
                 528 
                 CCCCCAUGCUUUGCGAGCA 
               
               
                   
               
               
                 336 
                 CGCAAAGCAUGGGGGCUAC 
                 529 
                 GUAGCCCCCAUGCUUUGCG 
               
               
                   
               
               
                 337 
                 AGCAUGGGGGCUACGUGUG 
                 530 
                 CACACGUAGCCCCCAUGCU 
               
               
                   
               
               
                 338 
                 GCAUGGGGGCUACGUGUGG 
                 531 
                 CCACACGUAGCCCCCAUGC 
               
               
                   
               
               
                 339 
                 CAUCUACAACCCUCGCAAC 
                 532 
                 GUUGCGAGGGUUGUAGAUG 
               
               
                   
               
               
                 340 
                 AUCUACAACCCUCGCAACC 
                 533 
                 GGUUGCGAGGGUUGUAGAU 
               
               
                   
               
               
                 341 
                 CUACAACCCUCGCAACCUG 
                 534 
                 CAGGUUGCGAGGGUUGUAG 
               
               
                   
               
               
                 342 
                 UACAACCCUCGCAACCUGC 
                 535 
                 GCAGGUUGCGAGGGUUGUA 
               
               
                   
               
               
                 343 
                 UUUGAUAGCAGUGGCAAGG 
                 536 
                 CCUUGCCACUGCUAUCAAA 
               
               
                   
               
               
                 344 
                 AGUAACUUCCUAUUCACCA 
                 537 
                 UGGUGAAUAGGAAGUUACU 
               
               
                   
               
               
                 345 
                 UCGGGAAUCAGAACUUCGA 
                 538 
                 UCGAAGUUCUGAUUCCCGA 
               
               
                   
               
               
                 346 
                 CUGCUCCACGCCCAAUAGC 
                 539 
                 GCUAUUGGGCGUGGAGCAG 
               
               
                   
               
               
                 347 
                 UGCUCCACGCCCAAUAGCC 
                 540 
                 GGCUAUUGGGCGUGGAGCA 
               
               
                   
               
               
                 348 
                 GCUCCACGCCCAAUAGCCC 
                 541 
                 GGGCUAUUGGGCGUGGAGC 
               
               
                   
               
               
                 349 
                 ACGCCCAAUAGCCCUGAAG 
                 542 
                 CUUCAGGGCUAUUGGGCGU 
               
               
                   
               
               
                 350 
                 CAUCUUUGGAUAACGACCU 
                 543 
                 AGGUCGUUAUCCAAAGAUG 
               
               
                   
               
               
                 351 
                 CAAUGCAGUACCCAGACGG 
                 544 
                 CCGUCUGGGUACUGCAUUG 
               
               
                   
               
               
                 352 
                 AUGCAGUACCCAGACGGAU 
                 545 
                 AUCCGUCUGGGUACUGCAU 
               
               
                   
               
               
                 353 
                 AGUACCCAGACGGAUUUCA 
                 546 
                 UGAAAUCCGUCUGGGUACU 
               
               
                   
               
               
                 354 
                 CUGUAGCCCCGCACAGUCC 
                 547 
                 GGACUGUGCGGGGCUACAG 
               
               
                   
               
               
                 355 
                 AUCUUCUUUGAUGCCGGAA 
                 548 
                 UUCCGGCAUCAAAGAAGAU 
               
               
                   
               
               
                 356 
                 CUUUGAUGCCGGAAGCAAA 
                 549 
                 UUUGCUUCCGGCAUCAAAG 
               
               
                   
               
               
                 357 
                 GAUGCCGGAAGCAAAGCAU 
                 550 
                 AUGCUUUGCUUCCGGCAUC 
               
               
                   
               
               
                 358 
                 AUGCCGGAAGCAAAGCAUC 
                 551 
                 GAUGCUUUGCUUCCGGCAU 
               
               
                   
               
               
                 359 
                 GCCGGAAGCAAAGCAUCCC 
                 552 
                 GGGAUGCUUUGCUUCCGGC 
               
               
                   
               
               
                 360 
                 CCCCCAGAUCCACCAUUAC 
                 553 
                 GUAAUGGUGGAUCUGGGGG 
               
               
                   
               
               
                 361 
                 AGAUCCACCAUUACAUUUU 
                 554 
                 AAAAUGUAAUGGUGGAUCU 
               
               
                   
               
               
                 362 
                 AUUUUGGGCCCACAAAGUG 
                 555 
                 CACUUUGUGGGCCCAAAAU 
               
               
                   
               
               
                 363 
                 UUUUGGGCCCACAAAGUGG 
                 556 
                 CCACUUUGUGGGCCCAAAA 
               
               
                   
               
               
                 364 
                 UUUGGGCCCACAAAGUGGG 
                 557 
                 CCCACUUUGUGGGCCCAAA 
               
               
                   
               
               
                 365 
                 CCACAAAGUGGGCCGUCGG 
                 558 
                 CCGACGGCCCACUUUGUGG 
               
               
                   
               
               
                 366 
                 CACAAAGUGGGCCGUCGGG 
                 559 
                 CCCGACGGCCCACUUUGUG 
               
               
                   
               
               
                 367 
                 AGUGGGCCGUCGGGGAUCA 
                 560 
                 UGAUCCCCGACGGCCCACU 
               
               
                   
               
               
                 368 
                 AAAGGGUUUUGGGGCUCGA 
                 561 
                 UCGAGCCCCAAAACCCUUU 
               
               
                   
               
               
                 369 
                 GGCUCGAGGCCCAGACGUG 
                 562 
                 CACGUCUGGGCCUCGAGCC 
               
               
                   
               
               
                 370 
                 GCUCGAGGCCCAGACGUGC 
                 563 
                 GCACGUCUGGGCCUCGAGC 
               
               
                   
               
               
                 371 
                 CUCGAGGCCCAGACGUGCU 
                 564 
                 AGCACGUCUGGGCCUCGAG 
               
               
                   
               
               
                 372 
                 GGUAGCCCUCUCCAACAAG 
                 565 
                 CUUGUUGGAGAGGGCUACC 
               
               
                   
               
               
                 373 
                 CUUUGAUGCCGGACAAGCC 
                 566 
                 GGCUUGUCCGGCAUCAAAG 
               
               
                   
               
               
                 374 
                 UUUGAUGCCGGACAAGCCA 
                 567 
                 UGGCUUGUCCGGCAUCAAA 
               
               
                   
               
               
                 375 
                 UUGAUGCCGGACAAGCCAC 
                 568 
                 GUGGCUUGUCCGGCAUCAA 
               
               
                   
               
               
                 376 
                 GGACAAGCCACUGAGCGCA 
                 569 
                 UGCGCUCAGUGGCUUGUCC 
               
               
                   
               
               
                 377 
                 ACAAGCCACUGAGCGCAAA 
                 570 
                 UUUGCGCUCAGUGGCUUGU 
               
               
                   
               
               
                 378 
                 GGACUACAGCCUGUCGUCA 
                 571 
                 UGACGACAGGCUGUAGUCC 
               
               
                   
               
               
                 379 
                 GACUACAGCCUGUCGUCAG 
                 572 
                 CUGACGACAGGCUGUAGUC 
               
               
                   
               
               
                 380 
                 CUACAGCCUGUCGUCAGCC 
                 573 
                 GGCUGACGACAGGCUGUAG 
               
               
                   
               
               
                 381 
                 CCUGUCGUCAGCCCACAAG 
                 574 
                 CUUGUGGGCUGACGACAGG 
               
               
                   
               
               
                 382 
                 GCAUGGCAAGCCGGCUGCU 
                 575 
                 AGCAGCCGGCUUGCCAUGC 
               
               
                   
               
               
                 383 
                 CUGACCAGAUAUGACUGUG 
                 576 
                 CACAGUCAUAUCUGGUCAG 
               
               
                   
               
               
                 384 
                 GAUAUGACUGUGAGGUGAA 
                 577 
                 UUCACCUCACAGUCAUAUC 
               
               
                   
               
               
                 385 
                 GGUGAACGUGCCCGUGCUG 
                 578 
                 CAGCACGGGCACGUUCACC 
               
               
                   
               
               
                 386 
                 UACAAGAUGGACUUACCUG 
                 579 
                 CAGGUAAGUCCAUCUUGUA 
               
               
                   
               
               
                 387 
                 GGACUUACCUGGCAGACUU 
                 580 
                 AAGUCUGCCAGGUAAGUCC 
               
               
                   
               
               
                 388 
                 UUUUUCUGAGAUGCUCACU 
                 581 
                 AGUGAGCAUCUCAGAAAAA 
               
               
                   
               
               
                 389 
                 AGUACACAAUUGUUUUACC 
                 582 
                 GGUAAAACAAUUGUGUACU 
               
               
                   
               
               
                 390 
                 ACAAGUUUGGUGCAUGUCU 
                 583 
                 AGACAUGCACCAAACUUGU 
               
               
                   
               
               
                 391 
                 ACUAAAAAGAUUCCUCGUU 
                 584 
                 AACGAGGAAUCUUUUUAGU 
               
               
                   
               
               
                 392 
                 AGGGUCAACUCCAACGUAU 
                 585 
                 AUACGUUGGAGUUGACCCU 
               
               
                   
               
               
                 393 
                 GGGUCAACUCCAACGUAUG 
                 586 
                 CAUACGUUGGAGUUGACCC 
               
               
                   
               
               
                 394 
                 GUCAACUCCAACGUAUGUG 
                 587 
                 CACAUACGUUGGAGUUGAC 
               
               
                   
               
               
                 395 
                 UCAACUCCAACGUAUGUGG 
                 588 
                 CCACAUACGUUGGAGUUGA 
               
               
                   
               
               
                 396 
                 CAACUCCAACGUAUGUGGU 
                 589 
                 ACCACAUACGUUGGAGUUG 
               
               
                   
               
               
                 397 
                 CUCCAACGUAUGUGGUUAU 
                 590 
                 AUAACCACAUACGUUGGAG 
               
               
                   
               
               
                 398 
                 UCCAACGUAUGUGGUUAUC 
                 591 
                 GAUAACCACAUACGUUGGA 
               
               
                   
               
               
                 399 
                 CCAACGUAUGUGGUUAUCU 
                 592 
                 AGAUAACCACAUACGUUGG 
               
               
                   
               
               
                 400 
                 AACGUAUGUGGUUAUCUGU 
                 593 
                 ACAGAUAACCACAUACGUU 
               
               
                   
               
               
                 401 
                 UUAUAUCUGGGUUAAGUGU 
                 594 
                 ACACUUAACCCAGAUAUAA 
               
               
                   
               
               
                 402 
                 CCACGGCCUGUACGGACAC 
                 595 
                 GUGUCCGUACAGGCCGUGG 
               
               
                   
               
               
                 403 
                 ACGGCCUGUACGGACACUG 
                 596 
                 CAGUGUCCGUACAGGCCGU 
               
               
                   
               
               
                 404 
                 UGUCGGCUUUUUGCCAUCU 
                 597 
                 AGAUGGCAAAAAGCCGACA 
               
               
                   
               
               
                 405 
                 GUCGGCUUUUUGCCAUCUG 
                 598 
                 CAGAUGGCAAAAAGCCGAC 
               
               
                   
               
               
                 406 
                 AUCUGUGAUAUGCCAUAGG 
                 599 
                 CCUAUGGCAUAUCACAGAU 
               
               
                   
               
               
                 407 
                 UGCCAUAGGUGUGACAAUC 
                 600 
                 GAUUGUCACACCUAUGGCA 
               
               
                   
               
               
                 408 
                 CCAUAGGUGUGACAAUCCG 
                 601 
                 CGGAUUGUCACACCUAUGG 
               
               
                   
               
               
                 409 
                 CAUAGGUGUGACAAUCCGA 
                 602 
                 UCGGAUUGUCACACCUAUG 
               
               
                   
               
               
                 410 
                 AUAGGUGUGACAAUCCGAG 
                 603 
                 CUCGGAUUGUCACACCUAU 
               
               
                   
               
               
                 411 
                 GGUGUGACAAUCCGAGCAG 
                 604 
                 CUGCUCGGAUUGUCACACC 
               
               
                   
               
               
                 412 
                 ACAAUCCGAGCAGUGGAGU 
                 605 
                 ACUCCACUGCUCGGAUUGU 
               
               
                   
               
               
                 413 
                 CCGAGCAGUGGAGUCAUUC 
                 606 
                 GAAUGACUCCACUGCUCGG 
               
               
                   
               
               
                 414 
                 GGGAGCACUGCGCGCUAUC 
                 607 
                 GAUAGCGCGCAGUGCUCCC 
               
               
                   
               
               
                 415 
                 GGAGCACUGCGCGCUAUCC 
                 608 
                 GGAUAGCGCGCAGUGCUCC 
               
               
                   
               
               
                 416 
                 AGCACUGCGCGCUAUCCCC 
                 609 
                 GGGGAUAGCGCGCAGUGCU 
               
               
                   
               
               
                 417 
                 UAUUGCUGCCAAGAGGGUC 
                 610 
                 GACCCUCUUGGCAGCAAUA 
               
               
                   
               
               
                 418 
                 GGUCUGAUGGCACGUUGUG 
                 611 
                 CACAACGUGCCAUCAGACC 
               
               
                   
               
               
                 419 
                 CUGAUGGCACGUUGUGGGG 
                 612 
                 CCCCACAACGUGCCAUCAG 
               
               
                   
               
               
                 420 
                 GGCACGUUGUGGGGUCGGG 
                 613 
                 CCCGACCCCACAACGUGCC 
               
               
                   
               
               
                 421 
                 GCACGUUGUGGGGUCGGGG 
                 614 
                 CCCCGACCCCACAACGUGC 
               
               
                   
               
               
                 422 
                 CACGUUGUGGGGUCGGGGG 
                 615 
                 CCCCCGACCCCACAACGUG 
               
               
                   
               
               
                 423 
                 GCGGGGAAGUGCUCUAACU 
                 616 
                 AGUUAGAGCACUUCCCCGC 
               
               
                   
               
               
                 424 
                 CGGGGAAGUGCUCUAACUU 
                 617 
                 AAGUUAGAGCACUUCCCCG 
               
               
                   
               
               
                 425 
                 UUAAGGUUUUGUUGCUAGC 
                 618 
                 GCUAGCAACAAAACCUUAA 
               
               
                   
               
               
                 426 
                 GUUGCUAGCCCUUCAAGUG 
                 619 
                 CACUUGAAGGGCUAGCAAC 
               
               
                   
               
               
                 427 
                 GAGCUAUGUGACUCGGAUG 
                 620 
                 CAUCCGAGUCACAUAGCUC 
               
               
                   
               
               
                 428 
                 GCUAUGUGACUCGGAUGGU 
                 621 
                 ACCAUCCGAGUCACAUAGC 
               
               
                   
               
               
                 429 
                 CGGAUGGUCUUUCACACGG 
                 622 
                 CCGUGUGAAAGACCAUCCG 
               
               
                   
               
               
                 430 
                 GAUGGUCUUUCACACGGCA 
                 623 
                 UGCCGUGUGAAAGACCAUC 
               
               
                   
               
               
                 431 
                 UGGUCUUUCACACGGCACA 
                 624 
                 UGUGCCGUGUGAAAGACCA 
               
               
                   
               
               
                 432 
                 AACUACCAUGAGAUGGUUU 
                 625 
                 AAACCAUCUCAUGGUAGUU 
               
               
                   
               
               
                 433 
                 UACCAUGAGAUGGUUUAGA 
                 626 
                 UCUAAACCAUCUCAUGGUA 
               
               
                   
               
               
                 434 
                 CCAAGCUCACGACCUUGGA 
                 627 
                 UCCAAGGUCGUGAGCUUGG 
               
               
                   
               
               
                 435 
                 ACGACCUUGGAGCCCCGUG 
                 628 
                 CACGGGGCUCCAAGGUCGU 
               
               
                   
               
               
                 436 
                 GGGUAAGAGGGACGACACC 
                 629 
                 GGUGUCGUCCCUCUUACCC 
               
               
                   
               
               
                 437 
                 GGUAAGAGGGACGACACCU 
                 630 
                 AGGUGUCGUCCCUCUUACC 
               
               
                   
               
               
                 438 
                 GUAAGAGGGACGACACCUC 
                 631 
                 GAGGUGUCGUCCCUCUUAC 
               
               
                   
               
               
                 439 
                 UGGUUUUUCAAUACCAAUU 
                 632 
                 AAUUGGUAUUGAAAAACCA 
               
               
                   
               
               
                 440 
                 UUCAAUACCAAUUACAUGG 
                 633 
                 CCAUGUAAUUGGUAUUGAA 
               
               
                   
               
               
                 441 
                 AUACCAAUUACAUGGAACU 
                 634 
                 AGUUCCAUGUAAUUGGUAU 
               
               
                   
               
               
                 442 
                 CCAACUAUUUAGUAAGCCC 
                 635 
                 GGGCUUACUAAAUAGUUGG 
               
               
                   
               
               
                 443 
                 AACUAUUUAGUAAGCCCGG 
                 636 
                 CCGGGCUUACUAAAUAGUU 
               
               
                   
               
               
                 444 
                 ACUAUUUAGUAAGCCCGGA 
                 637 
                 UCCGGGCUUACUAAAUAGU 
               
               
                   
               
               
                 445 
                 AGAAAUUCCUUAGUCAUGG 
                 638 
                 CCAUGACUAAGGAAUUUCU 
               
               
                   
               
               
                 446 
                 CAUUAAGGGCAUUUUACCC 
                 639 
                 GGGUAAAAUGCCCUUAAUG 
               
               
                   
               
               
                 447 
                 UAAGGGCAUUUUACCCUUG 
                 640 
                 CAAGGGUAAAAUGCCCUUA 
               
               
                   
               
               
                 448 
                 AGCUUCAUAUUAACCCUAC 
                 641 
                 GUAGGGUUAAUAUGAAGCU 
               
               
                   
               
               
                 449 
                 UAUUAACCCUACCUGUCAA 
                 642 
                 UUGACAGGUAGGGUUAAUA 
               
               
                   
               
               
                 450 
                 UUAACCCUACCUGUCAACG 
                 643 
                 CGUUGACAGGUAGGGUUAA 
               
               
                   
               
               
                 451 
                 ACCCUACCUGUCAACGUAA 
                 644 
                 UUACGUUGACAGGUAGGGU 
               
               
                   
               
               
                 452 
                 CCCUACCUGUCAACGUAAC 
                 645 
                 GUUACGUUGACAGGUAGGG 
               
               
                   
               
               
                 453 
                 CCUACCUGUCAACGUAACG 
                 646 
                 CGUUACGUUGACAGGUAGG 
               
               
                   
               
               
                 454 
                 CUACCUGUCAACGUAACGA 
                 647 
                 UCGUUACGUUGACAGGUAG 
               
               
                   
               
               
                 455 
                 UACCUGUCAACGUAACGAU 
                 648 
                 AUCGUUACGUUGACAGGUA 
               
               
                   
               
               
                 456 
                 ACCUGUCAACGUAACGAUU 
                 649 
                 AAUCGUUACGUUGACAGGU 
               
               
                   
               
               
                 457 
                 CCUGUCAACGUAACGAUUU 
                 650 
                 AAAUCGUUACGUUGACAGG 
               
               
                   
               
               
                 458 
                 CUGUCAACGUAACGAUUUC 
                 651 
                 GAAAUCGUUACGUUGACAG 
               
               
                   
               
               
                 459 
                 UGUCAACGUAACGAUUUCA 
                 652 
                 UGAAAUCGUUACGUUGACA 
               
               
                   
               
               
                 460 
                 UCAACGUAACGAUUUCAUG 
                 653 
                 CAUGAAAUCGUUACGUUGA 
               
               
                   
               
               
                 461 
                 ACGUAACGAUUUCAUGAAC 
                 654 
                 GUUCAUGAAAUCGUUACGU 
               
               
                   
               
               
                 462 
                 UAUUAUAUUGUCGAAUUCC 
                 655 
                 GGAAUUCGACAAUAUAAUA 
               
               
                   
               
               
                 463 
                 UUAUAUUGUCGAAUUCCUA 
                 656 
                 UAGGAAUUCGACAAUAUAA 
               
               
                   
               
               
                 464 
                 UAUUGUCGAAUUCCUACUG 
                 657 
                 CAGUAGGAAUUCGACAAUA 
               
               
                   
               
               
                 465 
                 GAAUUCCUACUGACAACAU 
                 658 
                 AUGUUGUCAGUAGGAAUUC 
               
               
                   
               
               
                 466 
                 UCCUACUGACAACAUUAUA 
                 659 
                 UAUAAUGUUGUCAGUAGGA 
               
               
                   
               
               
                 467 
                 UAUAACUGUAUGGGAGCUU 
                 660 
                 AAGCUCCCAUACAGUUAUA 
               
               
                   
               
               
                 468 
                 UAACUGUAUGGGAGCUUAA 
                 661 
                 UUAAGCUCCCAUACAGUUA 
               
               
                   
               
               
                 469 
                 UGUAUGGGAGCUUAACUUU 
                 662 
                 AAAGUUAAGCUCCCAUACA 
               
               
                   
               
               
                 470 
                 UUGACACUGGUAUCUUAUU 
                 663 
                 AAUAAGAUACCAGUGUCAA 
               
               
                   
               
               
                 471 
                 AAGUAUUCUGAUCCUACCA 
                 664 
                 UGGUAGGAUCAGAAUACUU 
               
               
                   
               
               
                 472 
                 CAACGUAACGAUUUCAUGA 
                 665 
                 UUCAUGAAAUCGUUACGUU 
               
               
                   
                 AA 
                   
                 GGC 
               
               
                   
               
               
                 473 
                 UAUAUCAACGUAACGAUUU 
                 666 
                 UUCAUGAAAUCGUUACGUU 
               
               
                   
                 CAUGAAA 
                   
                 GGCU 
               
               
                   
               
               
                 474 
                 UAUAUCAACGUAACGAUUU 
                 667 
                 UUCAUGAAAUCGUUACGUU 
               
               
                   
                 CAUGAAA 
                   
                 GGCUAU 
               
               
                   
               
               
                 475 
                 UAUAUCAACGUAACGAUUU 
                 668 
                 UUCAUGAAAUCGUUACGUU 
               
               
                   
                 CAUGAAA 
                   
                 GGCUGU 
               
               
                   
               
               
                 476 
                 UAUAUCGACGUAACGAUUU 
                 669 
                 UUCAUGAAAUCGUUACGUC 
               
               
                   
                 CAUGAAA 
                   
                 GGCUAU 
               
               
                   
               
               
                 477 
                 UAUACGUAACGAUUUCAUG 
                 670 
                 UUCAUGAAAUCGUUACGU 
               
               
                   
                 AAA 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5B 
               
             
            
               
                   
               
               
                 Hif2α RNAi trigger sequences having modified 
               
               
                 nucleotides. 
               
            
           
           
               
               
               
               
               
            
               
                 Duplex 
                 SEQ 
                   
                 SEQ 
                   
               
               
                 ID 
                 ID 
                 Sense Strand Sequence 
                 ID 
                 Antisense Strand Sequence 
               
               
                 No. 
                 No. 
                 (5′ → 3′) 
                 No. 
                 (5′ → 3′) 
               
               
                   
               
               
                 2231 
                 671 
                 GfaGfaCfuGfuAfuGfgUfcAfgCfuAfdT 
                  858 
                 dTAfgCfuGfaCfcAfuAfcAfgUfcUfcdTsdT 
               
               
                   
               
               
                 2232 
                 672 
                 CfuCfcGfaCfuCfcUfuCfcGfaCfuAfdT 
                  859 
                 dTAfgUfcGfgAfaGfgAfgUfcGfgAfgdTsdT 
               
               
                   
               
               
                 2233 
                 673 
                 UfcCfgAfcUfcCfcAfgCfaUfuCfgAfdT 
                  860 
                 dTCfgAfaUfgCfuGfgGfaGfuCfgGfadTsdT 
               
               
                   
               
               
                 2234 
                 674 
                 CfgAfcUfcCfcAfgCfaUfuCfgAfgAfdT 
                  861 
                 dTCfuCfgAfaUfgCfuGfgGfaGfuCfgdTsdT 
               
               
                   
               
               
                 2235 
                 675 
                 GfaCfuCfcCfaGfcAfuUfcGfaGfcAfdT 
                  862 
                 dTGfcUfcGfaAfuGfcUfgGfgAfgUfcdTsdT 
               
               
                   
               
               
                 2236 
                 676 
                 CfaGfgUfgCfuCfgGfcGfuCfuGfaAfdT 
                  863 
                 dTUfcAfgAfcGfcCfgAfgCfaCfcUfgdTsdT 
               
               
                   
               
               
                 2237 
                 677 
                 GfuGfcUfcGfgCfgUfcUfgAfaCfgAfdT 
                  864 
                 dTCfgUfuCfaGfaCfgCfcGfaGfcAfcdTsdT 
               
               
                   
               
               
                 2238 
                 678 
                 UfcGfgCfgUfcUfgAfaCfgUfcUfcAfdT 
                  865 
                 dTGfaGfaCfgUfuCfaGfaCfgCfcGfadTsdT 
               
               
                   
               
               
                 2239 
                 679 
                 GfgCfgUfcUfgAfaCfgUfcUfcAfaAfdT 
                  866 
                 dTUfuGfaGfaCfgUfuCfaGfaCfgCfcdTsdT 
               
               
                   
               
               
                 2240 
                 680 
                 CfgUfcUfgAfaCfgUfcUfcAfaAfgAfdT 
                  867 
                 dTCfuUfuGfaGfaCfgUfuCfaGfaCfgdTsdT 
               
               
                   
               
               
                 2241 
                 681 
                 AfaAfaGfgAfgUfaGfcUfcGfgAfgAfdT 
                  868 
                 dTCfuCfcGfaGfcUfaCfuCfcUfuUfudTsdT 
               
               
                   
               
               
                 2242 
                 682 
                 GfgGfuUfuCfaUfuGfcCfgUfgGfuAfdT 
                  869 
                 dTAfcCfaCfgGfcAfaUfgAfaAfcCfcdTsdT 
               
               
                   
               
               
                 2243 
                 683 
                 UfuCfaUfgGfgAfcUfuAfcAfcAfgAfdT 
                  870 
                 dTCfuGfuGfuAfaGfuCfcCfaUfgAfadTsdT 
               
               
                   
               
               
                 2244 
                 684 
                 GfgGfaCfuUfaCfaCfaGfgUfgGfaAfdT 
                  871 
                 dTUfcCfaCfcUfgUfgUfaAfgUfcCfcdTsdT 
               
               
                   
               
               
                 2245 
                 685 
                 AfcAfcAfgGfuGfgAfgCfuAfaCfaAfdT 
                  872 
                 dTUfgUfuAfgCfuCfcAfcCfuGfuGfudTsdT 
               
               
                   
               
               
                 2246 
                 686 
                 GfaGfcUfaAfcAfgGfaCfaUfaGfuAfdT 
                  873 
                 dTAfcUfaUfgUfcCfuGfuUfaGfcUfcdTsdT 
               
               
                   
               
               
                 2247 
                 687 
                 GfcUfaAfcAfgGfaCfaUfaGfuAfuAfdT 
                  874 
                 dTAfuAfcUfaUfgUfcCfuGfuUfaGfcdTsdT 
               
               
                   
               
               
                 2248 
                 688 
                 CfuAfaCfaGfgAfcAfuAfgUfaUfcAfdT 
                  875 
                 dTGfaUfaCfuAfuGfuCfcUfgUfuAfgdTsdT 
               
               
                   
               
               
                 2249 
                 689 
                 GfgAfcAfuAfgUfaUfcUfuUfgAfcAfdT 
                  876 
                 dTGfuCfaAfaGfaUfaCfuAfuGfuCfcdTsdT 
               
               
                   
               
               
                 2250 
                 690 
                 UfcUfuUfgAfcUfuCfaCfuCfaUfcAfdT 
                  877 
                 dTGfaUfgAfgUfgAfaGfuCfaAfaGfadTsdT 
               
               
                   
               
               
                 2251 
                 691 
                 UfcAfcUfcAfuCfcCfuGfcGfaCfcAfdT 
                  878 
                 dTGfgUfcGfcAfgGfgAfuGfaGfuGfadTsdT 
               
               
                   
               
               
                 2252 
                 692 
                 GfaGfaUfuCfgUfgAfgAfaCfcUfgAfdT 
                  879 
                 dTCfaGfgUfuCfuCfaCfgAfaUfcUfcdTsdT 
               
               
                   
               
               
                 2253 
                 693 
                 UfuCfgUfgAfgAfaCfcUfgAfgUfcAfdT 
                  880 
                 dTGfaCfuCfaGfgUfuCfuCfaCfgAfadTsdT 
               
               
                   
               
               
                 2254 
                 694 
                 UfcGfuGfaGfaAfcCfuGfaGfuCfuAfdT 
                  881 
                 dTAfgAfcUfcAfgGfuUfcUfcAfcGfadTsdT 
               
               
                   
               
               
                 2255 
                 695 
                 GfaCfaUfgUfcCfaCfaGfaGfcGfgAfdT 
                  882 
                 dTCfcGfcUfcUfgUfgGfaCfaUfgUfcdTsdT 
               
               
                   
               
               
                 2256 
                 696 
                 GfcGfgGfaCfuUfcUfuCfaUfgAfgAfdT 
                  883 
                 dTCfuCfaUfgAfaGfaAfgUfcCfcGfcdTsdT 
               
               
                   
               
               
                 2257 
                 697 
                 GfgAfuGfaAfgUfgCfaCfgGfuCfaAfdT 
                  884 
                 dTUfgAfcCfgUfgCfaCfuUfcAfuCfcdTsdT 
               
               
                   
               
               
                 2258 
                 698 
                 CfaCfgGfuCfaCfcAfaCfaGfaGfgAfdT 
                  885 
                 dTCfcUfcUfgUfuGfgUfgAfcCfgUfgdTsdT 
               
               
                   
               
               
                 2259 
                 699 
                 UfcAfcCfaAfcAfgAfgGfcCfgUfaAfdT 
                  886 
                 dTUfaCfgGfcCfuCfuGfuUfgGfuGfadTsdT 
               
               
                   
               
               
                 2260 
                 700 
                 CfaCfcAfaCfaGfaGfgCfcGfuAfcAfdT 
                  887 
                 dTGfuAfcGfgCfcUfcUfgUfuGfgUfgdTsdT 
               
               
                   
               
               
                 2261 
                 701 
                 AfgGfcCfgUfaCfuGfuCfaAfcCfuAfdT 
                  888 
                 dTAfgGfuUfgAfcAfgUfaCfgGfcCfudTsdT 
               
               
                   
               
               
                 2262 
                 702 
                 UfcCfuCfaCfaAfuAfgUfcUfgUfgAfdT 
                  889 
                 dTCfaCfaGfaCfuAfuUfgUfgAfgGfadTsdT 
               
               
                   
               
               
                 2263 
                 703 
                 AfaUfaGfuCfuGfuGfuGfgCfuAfcAfdT 
                  890 
                 dTGfuAfgCfcAfcAfcAfgAfcUfaUfudTsdT 
               
               
                   
               
               
                 2264 
                 704 
                 CfaGfaAfcUfgAfuUfgGfuUfaCfcAfdT 
                  891 
                 dTGfgUfaAfcCfaAfuCfaGfuUfcUfgdTsdT 
               
               
                   
               
               
                 2265 
                 705 
                 AfgAfaCfuGfaUfuGfgUfuAfcCfaAfdT 
                  892 
                 dTUfgGfuAfaCfcAfaUfcAfgUfuCfudTsdT 
               
               
                   
               
               
                 2266 
                 706 
                 CfuGfaUfuGfgUfuAfcCfaCfcCfuAfdT 
                  893 
                 dTAfgGfgUfgGfuAfaCfcAfaUfcAfgdTsdT 
               
               
                   
               
               
                 2267 
                 707 
                 UfuGfgCfcGfcUfcAfgCfcUfaUfgAfdT 
                  894 
                 dTCfaUfaGfgCfuGfaGfcGfgCfcAfadTsdT 
               
               
                   
               
               
                 2268 
                 708 
                 UfaUfgAfaUfuCfuAfcCfaUfgCfgAfdT 
                  895 
                 dTCfgCfaUfgGfuAfgAfaUfuCfaUfadTsdT 
               
               
                   
               
               
                 2269 
                 709 
                 AfuGfaAfuUfcUfaCfcAfuGfcGfcAfdT 
                  896 
                 dTGfcGfcAfuGfgUfaGfaAfuUfcAfudTsdT 
               
               
                   
               
               
                 2270 
                 710 
                 UfgAfaUfuCfuAfcCfaUfgCfgCfuAfdT 
                  897 
                 dTAfgCfgCfaUfgGfuAfgAfaUfuCfadTsdT 
               
               
                   
               
               
                 2271 
                 711 
                 GfaAfuUfcUfaCfcAfuGfcGfcUfaAfdT 
                  898 
                 dTUfaGfcGfcAfuGfgUfaGfaAfuUfcdTsdT 
               
               
                   
               
               
                 2272 
                 712 
                 AfaUfuCfuAfcCfaUfgCfgCfuAfgAfdT 
                  899 
                 dTCfuAfgCfgCfaUfgGfuAfgAfaUfudTsdT 
               
               
                   
               
               
                 2273 
                 713 
                 UfcUfaCfcAfuGfcGfcUfaGfaCfuAfdT 
                  900 
                 dTAfgUfcUfaGfcGfcAfuGfgUfaGfadTsdT 
               
               
                   
               
               
                 2274 
                 714 
                 AfuGfcGfcUfaGfaCfuCfcGfaGfaAfdT 
                  901 
                 dTUfcUfcGfgAfgUfcUfaGfcGfcAfudTsdT 
               
               
                   
               
               
                 2275 
                 715 
                 UfgCfgCfuAfgAfcUfcCfgAfgAfaAfdT 
                  902 
                 dTUfuCfuCfgGfaGfuCfuAfgCfgCfadTsdT 
               
               
                   
               
               
                 2276 
                 716 
                 GfuAfaGfuGfgCfcAfgUfaCfcGfgAfdT 
                  903 
                 dTCfcGfgUfaCfuGfgCfcAfcUfuAfcdTsdT 
               
               
                   
               
               
                 2277 
                 717 
                 UfaAfgUfgGfcCfaGfuAfcCfgGfaAfdT 
                  904 
                 dTUfcCfgGfuAfcUfgGfcCfaCfuUfadTsdT 
               
               
                   
               
               
                 2278 
                 718 
                 CfcAfgUfaCfcGfgAfuGfcUfcGfcAfdT 
                  905 
                 dTGfcGfaGfcAfuCfcGfgUfaCfuGfgdTsdT 
               
               
                   
               
               
                 2279 
                 719 
                 AfgUfaCfcGfgAfuGfcUfcGfcAfaAfdT 
                  906 
                 dTUfuGfcGfaGfcAfuCfcGfgUfaCfudTsdT 
               
               
                   
               
               
                 2280 
                 720 
                 UfaCfcGfgAfuGfcUfcGfcAfaAfgAfdT 
                  907 
                 dTCfuUfuGfcGfaGfcAfuCfcGfgUfadTsdT 
               
               
                   
               
               
                 2281 
                 721 
                 UfgCfuCfgCfaAfaGfcAfuGfgGfgAfdT 
                  908 
                 dTCfcCfcAfuGfcUfuUfgCfgAfgCfadTsdT 
               
               
                   
               
               
                 2282 
                 722 
                 CfgCfaAfaGfcAfuGfgGfgGfcUfaAfdT 
                  909 
                 dTUfaGfcCfcCfcAfuGfcUfuUfgCfgdTsdT 
               
               
                   
               
               
                 2283 
                 723 
                 AfgCfaUfgGfgGfgCfuAfcGfuGfuAfdT 
                  910 
                 dTAfcAfcGfuAfgCfcCfcCfaUfgCfudTsdT 
               
               
                   
               
               
                 2284 
                 724 
                 GfcAfuGfgGfgGfcUfaCfgUfgUfgAfdT 
                  911 
                 dTCfaCfaCfgUfaGfcCfcCfcAfuGfcdTsdT 
               
               
                   
               
               
                 2285 
                 725 
                 CfaUfcUfaCfaAfcCfcUfcGfcAfaAfdT 
                  912 
                 dTUfuGfcGfaGfgGfuUfgUfaGfaUfgdTsdT 
               
               
                   
               
               
                 2286 
                 726 
                 AfuCfuAfcAfaCfcCfuCfgCfaAfcAfdT 
                  913 
                 dTGfuUfgCfgAfgGfgUfuGfuAfgAfudTsdT 
               
               
                   
               
               
                 2287 
                 727 
                 CfuAfcAfaCfcCfuCfgCfaAfcCfuAfdT 
                  914 
                 dTAfgGfuUfgCfgAfgGfgUfuGfuAfgdTsdT 
               
               
                   
               
               
                 2288 
                 728 
                 UfaCfaAfcCfcUfcGfcAfaCfcUfgAfdT 
                  915 
                 dTCfaGfgUfuGfcGfaGfgGfuUfgUfadTsdT 
               
               
                   
               
               
                 2289 
                 729 
                 UfuUfgAfuAfgCfaGfuGfgCfaAfgAfdT 
                  916 
                 dTCfuUfgCfcAfcUfgCfuAfuCfaAfadTsdT 
               
               
                   
               
               
                 2290 
                 730 
                 AfgUfaAfcUfuCfcUfaUfuCfaCfcAfdT 
                  917 
                 dTGfgUfgAfaUfaGfgAfaGfuUfaCfudTsdT 
               
               
                   
               
               
                 2291 
                 731 
                 UfcGfgGfaAfuCfaGfaAfcUfuCfgAfdT 
                  918 
                 dTCfgAfaGfuUfcUfgAfuUfcCfcGfadTsdT 
               
               
                   
               
               
                 2292 
                 732 
                 CfuGfcUfcCfaCfgCfcCfaAfuAfgAfdT 
                  919 
                 dTCfuAfuUfgGfgCfgUfgGfaGfcAfgdTsdT 
               
               
                   
               
               
                 2293 
                 733 
                 UfgCfuCfcAfcGfcCfcAfaUfaGfcAfdT 
                  920 
                 dTGfcUfaUfuGfgGfcGfuGfgAfgCfadTsdT 
               
               
                   
               
               
                 2294 
                 734 
                 GfcUfcCfaCfgCfcCfaAfuAfgCfcAfdT 
                  921 
                 dTGfgCfuAfuUfgGfgCfgUfgGfaGfcdTsdT 
               
               
                   
               
               
                 2295 
                 735 
                 AfcGfcCfcAfaUfaGfcCfcUfgAfaAfdT 
                  922 
                 dTUfuCfaGfgGfcUfaUfuGfgGfcGfudTsdT 
               
               
                   
               
               
                 2296 
                 736 
                 CfaUfcUfuUfgGfaUfaAfcGfaCfcAfdT 
                  923 
                 dTGfgUfcGfuUfaUfcCfaAfaGfaUfgdTsdT 
               
               
                   
               
               
                 2297 
                 737 
                 CfaAfuGfcAfgUfaCfcCfaGfaCfgAfdT 
                  924 
                 dTCfgUfcUfgGfgUfaCfuGfcAfuUfgdTsdT 
               
               
                   
               
               
                 2298 
                 738 
                 AfuGfcAfgUfaCfcCfaGfaCfgGfaAfdT 
                  925 
                 dTUfcCfgUfcUfgGfgUfaCfuGfcAfudTsdT 
               
               
                   
               
               
                 2299 
                 739 
                 AfgUfaCfcCfaGfaCfgGfaUfuUfcAfdT 
                  926 
                 dTGfaAfaUfcCfgUfcUfgGfgUfaCfudTsdT 
               
               
                   
               
               
                 2300 
                 740 
                 CfuGfuAfgCfcCfcGfcAfcAfgUfcAfdT 
                  927 
                 dTGfaCfuGfuGfcGfgGfgCfuAfcAfgdTsdT 
               
               
                   
               
               
                 2301 
                 741 
                 AfuCfuUfcUfuUfgAfuGfcCfgGfaAfdT 
                  928 
                 dTUfcCfgGfcAfuCfaAfaGfaAfgAfudTsdT 
               
               
                   
               
               
                 2302 
                 742 
                 CfuUfuGfaUfgCfcGfgAfaGfcAfaAfdT 
                  929 
                 dTUfuGfcUfuCfcGfgCfaUfcAfaAfgdTsdT 
               
               
                   
               
               
                 2303 
                 743 
                 GfaUfgCfcGfgAfaGfcAfaAfgCfaAfdT 
                  930 
                 dTUfgCfuUfuGfcUfuCfcGfgCfaUfcdTsdT 
               
               
                   
               
               
                 2304 
                 744 
                 AfuGfcCfgGfaAfgCfaAfaGfcAfuAfdT 
                  931 
                 dTAfuGfcUfuUfgCfuUfcCfgGfcAfudTsdT 
               
               
                   
               
               
                 2305 
                 745 
                 GfcCfgGfaAfgCfaAfaGfcAfuCfcAfdT 
                  932 
                 dTGfgAfuGfcUfuUfgCfuUfcCfgGfcdTsdT 
               
               
                   
               
               
                 2306 
                 746 
                 CfcCfcCfaGfaUfcCfaCfcAfuUfaAfdT 
                  933 
                 dTUfaAfuGfgUfgGfaUfcUfgGfgGfgdTsdT 
               
               
                   
               
               
                 2307 
                 747 
                 AfgAfuCfcAfcCfaUfuAfcAfuUfuAfdT 
                  934 
                 dTAfaAfuGfuAfaUfgGfuGfgAfuCfudTsdT 
               
               
                   
               
               
                 2308 
                 748 
                 AfuUfuUfgGfgCfcCfaCfaAfaGfuAfdT 
                  935 
                 dTAfcUfuUfgUfgGfgCfcCfaAfaAfudTsdT 
               
               
                   
               
               
                 2309 
                 749 
                 UfuUfuGfgGfcCfcAfcAfaAfgUfgAfdT 
                  936 
                 dTCfaCfuUfuGfuGfgGfcCfcAfaAfadTsdT 
               
               
                   
               
               
                 2310 
                 750 
                 UfuUfgGfgCfcCfaCfaAfaGfuGfgAfdT 
                  937 
                 dTCfcAfcUfuUfgUfgGfgCfcCfaAfadTsdT 
               
               
                   
               
               
                 2311 
                 751 
                 CfcAfcAfaAfgUfgGfgCfcGfuCfgAfdT 
                  938 
                 dTCfgAfcGfgCfcCfaCfuUfuGfuGfgdTsdT 
               
               
                   
               
               
                 2312 
                 752 
                 CfaCfaAfaGfuGfgGfcCfgUfcGfgAfdT 
                  939 
                 dTCfcGfaCfgGfcCfcAfcUfuUfgUfgdTsdT 
               
               
                   
               
               
                 2313 
                 753 
                 AfgUfgGfgCfcGfuCfgGfgGfaUfcAfdT 
                  940 
                 dTGfaUfcCfcCfgAfcGfgCfcCfaCfudTsdT 
               
               
                   
               
               
                 2314 
                 754 
                 AfaAfgGfgUfuUfuGfgGfgCfuCfgAfdT 
                  941 
                 dTCfgAfgCfcCfcAfaAfaCfcCfuUfudTsdT 
               
               
                   
               
               
                 2315 
                 755 
                 GfgCfuCfgAfgGfcCfcAfgAfcGfuAfdT 
                  942 
                 dTAfcGfuCfuGfgGfcCfuCfgAfgCfcdTsdT 
               
               
                   
               
               
                 2316 
                 756 
                 GfcUfcGfaGfgCfcCfaGfaCfgUfgAfdT 
                  943 
                 dTCfaCfgUfcUfgGfgCfcUfcGfaGfcdTsdT 
               
               
                   
               
               
                 2317 
                 757 
                 CfuCfgAfgGfcCfcAfgAfcGfuGfcAfdT 
                  944 
                 dTGfcAfcGfuCfuGfgGfcCfuCfgAfgdTsdT 
               
               
                   
               
               
                 2318 
                 758 
                 GfgUfaGfcCfcUfcUfcCfaAfcAfaAfdT 
                  945 
                 dTUfuGfuUfgGfaGfaGfgGfcUfaCfcdTsdT 
               
               
                   
               
               
                 2319 
                 759 
                 CfuUfuGfaUfgCfcGfgAfcAfaGfcAfdT 
                  946 
                 dTGfcUfuGfuCfcGfgCfaUfcAfaAfgdTsdT 
               
               
                   
               
               
                 2320 
                 760 
                 UfuUfgAfuGfcCfgGfaCfaAfgCfcAfdT 
                  947 
                 dTGfgCfuUfgUfcCfgGfcAfuCfaAfadTsdT 
               
               
                   
               
               
                 2321 
                 761 
                 UfuGfaUfgCfcGfgAfcAfaGfcCfaAfdT 
                  948 
                 dTUfgGfcUfuGfuCfcGfgCfaUfcAfadTsdT 
               
               
                   
               
               
                 2322 
                 762 
                 GfgAfcAfaGfcCfaCfuGfaGfcGfcAfdT 
                  949 
                 dTGfcGfcUfcAfgUfgGfcUfuGfuCfcdTsdT 
               
               
                   
               
               
                 2323 
                 763 
                 AfcAfaGfcCfaCfuGfaGfcGfcAfaAfdT 
                  950 
                 dTUfuGfcGfcUfcAfgUfgGfcUfuGfudTsdT 
               
               
                   
               
               
                 2324 
                 764 
                 GfgAfcUfaCfaGfcCfuGfuCfgUfcAfdT 
                  951 
                 dTGfaCfgAfcAfgGfcUfgUfaGfuCfcdTsdT 
               
               
                   
               
               
                 2325 
                 765 
                 GfaCfuAfcAfgCfcUfgUfcGfuCfaAfdT 
                  952 
                 dTUfgAfcGfaCfaGfgCfuGfuAfgUfcdTsdT 
               
               
                   
               
               
                 2326 
                 766 
                 CfuAfcAfgCfcUfgUfcGfuCfaGfcAfdT 
                  953 
                 dTGfcUfgAfcGfaCfaGfgCfuGfuAfgdTsdT 
               
               
                   
               
               
                 2327 
                 767 
                 CfcUfgUfcGfuCfaGfcCfcAfcAfaAfdT 
                  954 
                 dTUfuGfuGfgGfcUfgAfcGfaCfaGfgdTsdT 
               
               
                   
               
               
                 2328 
                 768 
                 GfcAfuGfgCfaAfgCfcGfgCfuGfcAfdT 
                  955 
                 dTGfcAfgCfcGfgCfuUfgCfcAfuGfcdTsdT 
               
               
                   
               
               
                 2329 
                 769 
                 CfuGfaCfcAfgAfuAfuGfaCfuGfuAfdT 
                  956 
                 dTAfcAfgUfcAfuAfuCfuGfgUfcAfgdTsdT 
               
               
                   
               
               
                 2330 
                 770 
                 GfaUfaUfgAfcUfgUfgAfgGfuGfaAfdT 
                  957 
                 dTUfcAfcCfuCfaCfaGfuCfaUfaUfcdTsdT 
               
               
                   
               
               
                 2331 
                 771 
                 GfgUfgAfaCfgUfgCfcCfgUfgCfuAfdT 
                  958 
                 dTAfgCfaCfgGfgCfaCfgUfuCfaCfcdTsdT 
               
               
                   
               
               
                 2332 
                 772 
                 UfaCfaAfgAfuGfgAfcUfuAfcCfuAfdT 
                  959 
                 dTAfgGfuAfaGfuCfcAfuCfuUfgUfadTsdT 
               
               
                   
               
               
                 2333 
                 773 
                 GfgAfcUfuAfcCfuGfgCfaGfaCfuAfdT 
                  960 
                 dTAfgUfcUfgCfcAfgGfuAfaGfuCfcdTsdT 
               
               
                   
               
               
                 2334 
                 774 
                 UfuUfuUfcUfgAfgAfuGfcUfcAfcAfdT 
                  961 
                 dTGfuGfaGfcAfuCfuCfaGfaAfaAfadTsdT 
               
               
                   
               
               
                 2335 
                 775 
                 AfgUfaCfaCfaAfuUfgUfuUfuAfcAfdT 
                  962 
                 dTGfuAfaAfaCfaAfuUfgUfgUfaCfudTsdT 
               
               
                   
               
               
                 2336 
                 776 
                 AfcAfaGfuUfuGfgUfgCfaUfgUfcAfdT 
                  963 
                 dTGfaCfaUfgCfaCfcAfaAfcUfuGfudTsdT 
               
               
                   
               
               
                 2337 
                 777 
                 AfcUfaAfaAfaGfaUfuCfcUfcGfuAfdT 
                  964 
                 dTAfcGfaGfgAfaUfcUfuUfuUfaGfudTsdT 
               
               
                   
               
               
                 2338 
                 778 
                 AfgGfgUfcAfaCfuCfcAfaCfgUfaAfdT 
                  965 
                 dTUfaCfgUfuGfgAfgUfuGfaCfcCfudTsdT 
               
               
                   
               
               
                 2339 
                 779 
                 GfgGfuCfaAfcUfcCfaAfcGfuAfuAfdT 
                  966 
                 dTAfuAfcGfuUfgGfaGfuUfgAfcCfcdTsdT 
               
               
                   
               
               
                 2340 
                 780 
                 GfuCfaAfcUfcCfaAfcGfuAfuGfuAfdT 
                  967 
                 dTAfcAfuAfcGfuUfgGfaGfuUfgAfcdTsdT 
               
               
                   
               
               
                 2341 
                 781 
                 UfcAfaCfuCfcAfaCfgUfaUfgUfgAfdT 
                  968 
                 dTCfaCfaUfaCfgUfuGfgAfgUfuGfadTsdT 
               
               
                   
               
               
                 2342 
                 782 
                 CfaAfcUfcCfaAfcGfuAfuGfuGfgAfdT 
                  969 
                 dTCfcAfcAfuAfcGfuUfgGfaGfuUfgdTsdT 
               
               
                   
               
               
                 2343 
                 783 
                 CfuCfcAfaCfgUfaUfgUfgGfuUfaAfdT 
                  970 
                 dTUfaAfcCfaCfaUfaCfgUfuGfgAfgdTsdT 
               
               
                   
               
               
                 2344 
                 784 
                 UfcCfaAfcGfuAfuGfuGfgUfuAfuAfdT 
                  971 
                 dTAfuAfaCfcAfcAfuAfcGfuUfgGfadTsdT 
               
               
                   
               
               
                 2345 
                 785 
                 CfcAfaCfgUfaUfgUfgGfuUfaUfcAfdT 
                  972 
                 dTGfaUfaAfcCfaCfaUfaCfgUfuGfgdTsdT 
               
               
                   
               
               
                 2346 
                 786 
                 AfaCfgUfaUfgUfgGfuUfaUfcUfgAfdT 
                  973 
                 dTCfaGfaUfaAfcCfaCfaUfaCfgUfudTsdT 
               
               
                   
               
               
                 2347 
                 787 
                 UfuAfuAfuCfuGfgGfuUfaAfgUfgAfdT 
                  974 
                 dTCfaCfuUfaAfcCfcAfgAfuAfuAfadTsdT 
               
               
                   
               
               
                 2348 
                 788 
                 CfcAfcGfgCfcUfgUfaCfgGfaCfaAfdT 
                  975 
                 dTUfgUfcCfgUfaCfaGfgCfcGfuGfgdTsdT 
               
               
                   
               
               
                 2349 
                 789 
                 AfcGfgCfcUfgUfaCfgGfaCfaCfuAfdT 
                  976 
                 dTAfgUfgUfcCfgUfaCfaGfgCfcGfudTsdT 
               
               
                   
               
               
                 2350 
                 790 
                 UfgUfcGfgCfuUfuUfuGfcCfaUfcAfdT 
                  977 
                 dTGfaUfgGfcAfaAfaAfgCfcGfaCfadTsdT 
               
               
                   
               
               
                 2351 
                 791 
                 GfuCfgGfcUfuUfuUfgCfcAfuCfuAfdT 
                  978 
                 dTAfgAfuGfgCfaAfaAfaGfcCfgAfcdTsdT 
               
               
                   
               
               
                 2352 
                 792 
                 AfuCfuGfuGfaUfaUfgCfcAfuAfgAfdT 
                  979 
                 dTCfuAfuGfgCfaUfaUfcAfcAfgAfudTsdT 
               
               
                   
               
               
                 2353 
                 793 
                 UfgCfcAfuAfgGfuGfuGfaCfaAfuAfdT 
                  980 
                 dTAfuUfgUfcAfcAfcCfuAfuGfgCfadTsdT 
               
               
                   
               
               
                 2354 
                 794 
                 CfcAfuAfgGfuGfuGfaCfaAfuCfcAfdT 
                  981 
                 dTGfgAfuUfgUfcAfcAfcCfuAfuGfgdTsdT 
               
               
                   
               
               
                 2355 
                 795 
                 CfaUfaGfgUfgUfgAfcAfaUfcCfgAfdT 
                  982 
                 dTCfgGfaUfuGfuCfaCfaCfcUfaUfgdTsdT 
               
               
                   
               
               
                 2356 
                 796 
                 AfuAfgGfuGfuGfaCfaAfuCfcGfaAfdT 
                  983 
                 dTUfcGfgAfuUfgUfcAfcAfcCfuAfudTsdT 
               
               
                   
               
               
                 2357 
                 797 
                 GfgUfgUfgAfcAfaUfcCfgAfgCfaAfdT 
                  984 
                 dTUfgCfuCfgGfaUfuGfuCfaCfaCfcdTsdT 
               
               
                   
               
               
                 2358 
                 798 
                 AfcAfaUfcCfgAfgCfaGfuGfgAfgAfdT 
                  985 
                 dTCfuCfcAfcUfgCfuCfgGfaUfuGfudTsdT 
               
               
                   
               
               
                 2359 
                 799 
                 CfcGfaGfcAfgUfgGfaGfuCfaUfuAfdT 
                  986 
                 dTAfaUfgAfcUfcCfaCfuGfcUfcGfgdTsdT 
               
               
                   
               
               
                 2360 
                 800 
                 GfgGfaGfcAfcUfgCfgCfgCfuAfuAfdT 
                  987 
                 dTAfuAfgCfgCfgCfaGfuGfcUfcCfcdTsdT 
               
               
                   
               
               
                 2361 
                 801 
                 GfgAfgCfaCfuGfcGfcGfcUfaUfcAfdT 
                  988 
                 dTGfaUfaGfcGfcGfcAfgUfgCfuCfcdTsdT 
               
               
                   
               
               
                 2362 
                 802 
                 AfgCfaCfuGfcGfcGfcUfaUfcCfcAfdT 
                  989 
                 dTGfgGfaUfaGfcGfcGfcAfgUfgCfudTsdT 
               
               
                   
               
               
                 2363 
                 803 
                 UfaUfuGfcUfgCfcAfaGfaGfgGfuAfdT 
                  990 
                 dTAfcCfcUfcUfuGfgCfaGfcAfaUfadTsdT 
               
               
                   
               
               
                 2364 
                 804 
                 GfgUfcUfgAfuGfgCfaCfgUfuGfuAfdT 
                  991 
                 dTAfcAfaCfgUfgCfcAfuCfaGfaCfcdTsdT 
               
               
                   
               
               
                 2365 
                 805 
                 CfuGfaUfgGfcAfcGfuUfgUfgGfgAfdT 
                  992 
                 dTCfcCfaCfaAfcGfuGfcCfaUfcAfgdTsdT 
               
               
                   
               
               
                 2366 
                 806 
                 GfgCfaCfgUfuGfuGfgGfgUfcGfgAfdT 
                  993 
                 dTCfcGfaCfcCfcAfcAfaCfgUfgCfcdTsdT 
               
               
                   
               
               
                 2367 
                 807 
                 GfcAfcGfuUfgUfgGfgGfuCfgGfgAfdT 
                  994 
                 dTCfcCfgAfcCfcCfaCfaAfcGfuGfcdTsdT 
               
               
                   
               
               
                 2368 
                 808 
                 CfaCfgUfuGfuGfgGfgUfcGfgGfgAfdT 
                  995 
                 dTCfcCfcGfaCfcCfcAfcAfaCfgUfgdTsdT 
               
               
                   
               
               
                 2369 
                 809 
                 GfcGfgGfgAfaGfuGfcUfcUfaAfcAfdT 
                  996 
                 dTGfuUfaGfaGfcAfcUfuCfcCfcGfcdTsdT 
               
               
                   
               
               
                 2370 
                 810 
                 CfgGfgGfaAfgUfgCfuCfuAfaCfuAfdT 
                  997 
                 dTAfgUfuAfgAfgCfaCfuUfcCfcCfgdTsdT 
               
               
                   
               
               
                 2371 
                 811 
                 UfuAfaGfgUfuUfuGfuUfgCfuAfgAfdT 
                  998 
                 dTCfuAfgCfaAfcAfaAfaCfcUfuAfadTsdT 
               
               
                   
               
               
                 2372 
                 812 
                 GfuUfgCfuAfgCfcCfuUfcAfaGfuAfdT 
                  999 
                 dTAfcUfuGfaAfgGfgCfuAfgCfaAfcdTsdT 
               
               
                   
               
               
                 2373 
                 813 
                 GfaGfcUfaUfgUfgAfcUfcGfgAfuAfdT 
                 1000 
                 dTAfuCfcGfaGfuCfaCfaUfaGfcUfcdTsdT 
               
               
                   
               
               
                 2374 
                 814 
                 GfcUfaUfgUfgAfcUfcGfgAfuGfgAfdT 
                 1001 
                 dTCfcAfuCfcGfaGfuCfaCfaUfaGfcdTsdT 
               
               
                   
               
               
                 2375 
                 815 
                 CfgGfaUfgGfuCfuUfuCfaCfaCfgAfdT 
                 1002 
                 dTCfgUfgUfgAfaAfgAfcCfaUfcCfgdTsdT 
               
               
                   
               
               
                 2376 
                 816 
                 GfaUfgGfuCfuUfuCfaCfaCfgGfcAfdT 
                 1003 
                 dTGfcCfgUfgUfgAfaAfgAfcCfaUfcdTsdT 
               
               
                   
               
               
                 2377 
                 817 
                 UfgGfuCfuUfuCfaCfaCfgGfcAfcAfdT 
                 1004 
                 dTGfuGfcCfgUfgUfgAfaAfgAfcCfadTsdT 
               
               
                   
               
               
                 2378 
                 818 
                 AfaCfuAfcCfaUfgAfgAfuGfgUfuAfdT 
                 1005 
                 dTAfaCfcAfuCfuCfaUfgGfuAfgUfudTsdT 
               
               
                   
               
               
                 2379 
                 819 
                 UfaCfcAfuGfaGfaUfgGfuUfuAfgAfdT 
                 1006 
                 dTCfuAfaAfcCfaUfcUfcAfuGfgUfadTsdT 
               
               
                   
               
               
                 2380 
                 820 
                 CfcAfaGfcUfcAfcGfaCfcUfuGfgAfdT 
                 1007 
                 dTCfcAfaGfgUfcGfuGfaGfcUfuGfgdTsdT 
               
               
                   
               
               
                 2381 
                 821 
                 AfcGfaCfcUfuGfgAfgCfcCfcGfuAfdT 
                 1008 
                 dTAfcGfgGfgCfuCfcAfaGfgUfcGfudTsdT 
               
               
                   
               
               
                 2382 
                 822 
                 GfgGfuAfaGfaGfgGfaCfgAfcAfcAfdT 
                 1009 
                 dTGfuGfuCfgUfcCfcUfcUfuAfcCfcdTsdT 
               
               
                   
               
               
                 2383 
                 823 
                 GfgUfaAfgAfgGfgAfcGfaCfaCfcAfdT 
                 1010 
                 dTGfgUfgUfcGfuCfcCfuCfuUfaCfcdTsdT 
               
               
                   
               
               
                 2384 
                 824 
                 GfuAfaGfaGfgGfaCfgAfcAfcCfuAfdT 
                 1011 
                 dTAfgGfuGfuCfgUfcCfcUfcUfuAfcdTsdT 
               
               
                   
               
               
                 2385 
                 825 
                 UfgGfuUfuUfuCfaAfuAfcCfaAfuAfdT 
                 1012 
                 dTAfuUfgGfuAfuUfgAfaAfaAfcCfadTsdT 
               
               
                   
               
               
                 2386 
                 826 
                 UfuCfaAfuAfcCfaAfuUfaCfaUfgAfdT 
                 1013 
                 dTCfaUfgUfaAfuUfgGfuAfuUfgAfadTsdT 
               
               
                   
               
               
                 2387 
                 827 
                 AfuAfcCfaAfuUfaCfaUfgGfaAfcAfdT 
                 1014 
                 dTGfuUfcCfaUfgUfaAfuUfgGfuAfudTsdT 
               
               
                   
               
               
                 2388 
                 828 
                 CfcAfaCfuAfuUfuAfgUfaAfgCfcAfdT 
                 1015 
                 dTGfgCfuUfaCfuAfaAfuAfgUfuGfgdTsdT 
               
               
                   
               
               
                 2389 
                 829 
                 AfaCfuAfuUfuAfgUfaAfgCfcCfgAfdT 
                 1016 
                 dTCfgGfgCfuUfaCfuAfaAfuAfgUfudTsdT 
               
               
                   
               
               
                 2390 
                 830 
                 AfcUfaUfuUfaGfuAfaGfcCfcGfgAfdT 
                 1017 
                 dTCfcGfgGfcUfuAfcUfaAfaUfaGfudTsdT 
               
               
                   
               
               
                 2391 
                 831 
                 AfgAfaAfuUfcCfuUfaGfuCfaUfgAfdT 
                 1018 
                 dTCfaUfgAfcUfaAfgGfaAfuUfuCfudTsdT 
               
               
                   
               
               
                 2392 
                 832 
                 CfaUfuAfaGfgGfcAfuUfuUfaCfcAfdT 
                 1019 
                 dTGfgUfaAfaAfuGfcCfcUfuAfaUfgdTsdT 
               
               
                   
               
               
                 2393 
                 833 
                 UfaAfgGfgCfaUfuUfuAfcCfcUfuAfdT 
                 1020 
                 dTAfaGfgGfuAfaAfaUfgCfcCfuUfadTsdT 
               
               
                   
               
               
                 2394 
                 834 
                 AfgCfuUfcAfuAfuUfaAfcCfcUfaAfdT 
                 1021 
                 dTUfaGfgGfuUfaAfuAfuGfaAfgCfudTsdT 
               
               
                   
               
               
                 2395 
                 835 
                 UfaUfuAfaCfcCfuAfcCfuGfuCfaAfdT 
                 1022 
                 dTUfgAfcAfgGfuAfgGfgUfuAfaUfadTsdT 
               
               
                   
               
               
                 2396 
                 836 
                 UfuAfaCfcCfuAfcCfuGfuCfaAfcAfdT 
                 1023 
                 dTGfuUfgAfcAfgGfuAfgGfgUfuAfadTsdT 
               
               
                   
               
               
                 2397 
                 837 
                 AfcCfcUfaCfcUfgUfcAfaCfgUfaAfdT 
                 1024 
                 dTUfaCfgUfuGfaCfaGfgUfaGfgGfudTsdT 
               
               
                   
               
               
                 2398 
                 838 
                 CfcCfuAfcCfuGfuCfaAfcGfuAfaAfdT 
                 1025 
                 dTUfuAfcGfuUfgAfcAfgGfuAfgGfgdTsdT 
               
               
                   
               
               
                 2399 
                 839 
                 CfcUfaCfcUfgUfcAfaCfgUfaAfcAfdT 
                 1026 
                 dTGfuUfaCfgUfuGfaCfaGfgUfaGfgdTsdT 
               
               
                   
               
               
                 2400 
                 840 
                 CfuAfcCfuGfuCfaAfcGfuAfaCfgAfdT 
                 1027 
                 dTCfgUfuAfcGfuUfgAfcAfgGfuAfgdTsdT 
               
               
                   
               
               
                 2401 
                 841 
                 UfaCfcUfgUfcAfaCfgUfaAfcGfaAfdT 
                 1028 
                 dTUfcGfuUfaCfgUfuGfaCfaGfgUfadTsdT 
               
               
                   
               
               
                 2402 
                 842 
                 AfcCfuGfuCfaAfcGfuAfaCfgAfuAfdT 
                 1029 
                 dTAfuCfgUfuAfcGfuUfgAfcAfgGfudTsdT 
               
               
                   
               
               
                 2403 
                 843 
                 CfcUfgUfcAfaCfgUfaAfcGfaUfuAfdT 
                 1030 
                 dTAfaUfcGfuUfaCfgUfuGfaCfaGfgdTsdT 
               
               
                   
               
               
                 2404 
                 844 
                 CfuGfuCfaAfcGfuAfaCfgAfuUfuAfdT 
                 1031 
                 dTAfaAfuCfgUfuAfcGfuUfgAfcAfgdTsdT 
               
               
                   
               
               
                 2405 
                 845 
                 UfgUfcAfaCfgUfaAfcGfaUfuUfcAfdT 
                 1032 
                 dTGfaAfaUfcGfuUfaCfgUfuGfaCfadTsdT 
               
               
                   
               
               
                 2406 
                 846 
                 UfcAfaCfgUfaAfcGfaUfuUfcAfuAfdT 
                 1033 
                 dTAfuGfaAfaUfcGfuUfaCfgUfuGfadTsdT 
               
               
                   
               
               
                 2407 
                 847 
                 AfcGfuAfaCfgAfuUfuCfaUfgAfaAfdT 
                 1034 
                 dTUfuCfaUfgAfaAfuCfgUfuAfcGfudTsdT 
               
               
                   
               
               
                 2408 
                 848 
                 UfaUfuAfuAfuUfgUfcGfaAfuUfcAfdT 
                 1035 
                 dTGfaAfuUfcGfaCfaAfuAfuAfaUfadTsdT 
               
               
                   
               
               
                 2409 
                 849 
                 UfuAfuAfuUfgUfcGfaAfuUfcCfuAfdT 
                 1036 
                 dTAfgGfaAfuUfcGfaCfaAfuAfuAfadTsdT 
               
               
                   
               
               
                 2410 
                 850 
                 UfaUfuGfuCfgAfaUfuCfcUfaCfuAfdT 
                 1037 
                 dTAfgUfaGfgAfaUfuCfgAfcAfaUfadTsdT 
               
               
                   
               
               
                 2411 
                 851 
                 GfaAfuUfcCfuAfcUfgAfcAfaCfaAfdT 
                 1038 
                 dTUfgUfuGfuCfaGfuAfgGfaAfuUfcdTsdT 
               
               
                   
               
               
                 2412 
                 852 
                 UfcCfuAfcUfgAfcAfaCfaUfuAfuAfdT 
                 1039 
                 dTAfuAfaUfgUfuGfuCfaGfuAfgGfadTsdT 
               
               
                   
               
               
                 2413 
                 853 
                 UfaUfaAfcUfgUfaUfgGfgAfgCfuAfdT 
                 1040 
                 dTAfgCfuCfcCfaUfaCfaGfuUfaUfadTsdT 
               
               
                   
               
               
                 2414 
                 854 
                 UfaAfcUfgUfaUfgGfgAfgCfuUfaAfdT 
                 1041 
                 dTUfaAfgCfuCfcCfaUfaCfaGfuUfadTsdT 
               
               
                   
               
               
                 2415 
                 855 
                 UfgUfaUfgGfgAfgCfuUfaAfcUfuAfdT 
                 1042 
                 dTAfaGfuUfaAfgCfuCfcCfaUfaCfadTsdT 
               
               
                   
               
               
                 2416 
                 856 
                 UfuGfaCfaCfuGfgUfaUfcUfuAfuAfdT 
                 1043 
                 dTAfuAfaGfaUfaCfcAfgUfgUfcAfadTsdT 
               
               
                   
               
               
                 2417 
                 857 
                 AfaGfuAfuUfcUfgAfuCfcUfaCfcAfdT 
                 1044 
                 dTGfgUfaGfgAfuCfaGfaAfuAfcUfudTsdT 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5C 
               
             
            
               
                   
               
               
                 Efficacy screen results of Hif2α RNAi triggers in viro, as determined by dual-luciferase reporter assay.  
               
            
           
           
               
               
               
               
            
               
                 duplex 
                 Relative R luc -Hif2α 
                 AD  
                 Relative R luc -Hif2α 
               
            
           
           
               
               
               
               
               
               
            
               
                 number 
                 1 nM 
                 0.1 nM 
                 number 
                 1 nM 
                 0.1 nM 
               
               
                   
               
               
                 2231 
                 0.491 ± 0.198 
                 0.544 ± 0.368 
                 2325 
                 1.379 ± 0.275 
                 1.304 ± 0.134 
               
               
                 2232 
                 0.468 ± 0.032 
                 0.684 ± 0.061 
                 2326 
                 0.546 ± 0.083 
                 0.660 ± 0.114 
               
               
                 2233 
                 0.862 ± 0.125 
                 0.913 ± 0.019 
                 2327 
                 1.073 ± 0.089 
                 1.339 ± 0.179 
               
               
                 2234 
                 0.388 ± 0.046 
                 0.508 ± 0.148 
                 2328 
                 1.192 ± 0.144 
                 1.291 ± 0.109 
               
               
                 2235 
                 0.857 ± 0.090 
                 0.743 ± 0.129 
                 2329 
                 0.456 ± 0.064 
                 0.807 ± 0.117 
               
               
                 2236 
                 0.761 ± 0.042 
                 0.693 ± 0.071 
                 2330 
                 0.464 ± 0.035 
                 1.097 ± 0.416 
               
               
                 2237 
                 0.978 ± 0.083 
                 0.746 ± 0.029 
                 2331 
                 0.783 ± 0.080 
                 1.002 ± 0.321 
               
               
                 2238 
                 0.148 ± 0.024 
                 0.208 ± 0.023 
                 2332 
                 0.871 ± 0.235 
                 1.174 ± 0.027 
               
               
                 2239 
                 0.157 ± 0.017 
                 0.225 ± 0.022 
                 2333 
                 0.291 ± 0.019 
                 0.684 ± 0.147 
               
               
                 2240 
                 0.845 ± 0.052 
                 0.841 ± 0.048 
                 2334 
                 0.389 ± 0.044 
                 0.672 ± 0.082 
               
               
                 2241 
                 0.270 ± 0.068 
                 0.385 ± 0.028 
                 2335 
                 0.104 ± 0.013 
                 0.311 ± 0.032 
               
               
                 2242 
                 0.222 ± 0.064 
                 0.411 ± 0.019 
                 2336 
                 0.299 ± 0.034 
                 0.783 ± 0.037 
               
               
                 2243 
                 0.694 ± 0.107 
                 0.688 ± 0.059 
                 2337 
                 0.131 ± 0.033 
                 0.334 ± 0.066 
               
               
                 2244 
                 0.915 ± 0.115 
                 0.760 ± 0.050 
                 2338 
                 0.334 ± 0.091 
                 0.743 ± 0.070 
               
               
                 2245 
                 0.727 ± 0.066 
                 0.761 ± 0.039 
                 2339 
                 0.189 ± 0.028 
                 0.523 ± 0.134 
               
               
                 2246 
                 0.327 ± 0.042 
                 0.509 ± 0.044 
                 2340 
                 0.444 ± 0.039 
                 0.920 ± 0.114 
               
               
                 2247 
                 0.231 ± 0.048 
                 0.439 ± 0.082 
                 2341 
                 0.202 ± 0.018 
                 0.378 ± 0.116 
               
               
                 2248 
                 0.148 ± 0.036 
                 0.215 ± 0.007 
                 2342 
                 0.549 ± 0.041 
                 1.058 ± 0.064 
               
               
                 2249 
                 0.190 ± 0.028 
                 0.303 ± 0.042 
                 2343 
                 0.254 ± 0.009 
                 0.620 ± 0.208 
               
               
                 2250 
                 0.139 ± 0.046 
                 0.255 ± 0.020 
                 2344 
                 0.276 ± 0.033 
                 0.570 ± 0.071 
               
               
                 2251 
                 0.872 ± 0.121 
                 0.857 ± 0.087 
                 2345 
                 0.129 ± 0.026 
                 0.296 ± 0.096 
               
               
                 2252 
                 0.592 ± 0.061 
                 0.696 ± 0.096 
                 2346 
                 0.273 ± 0.012 
                 0.523 ± 0.133 
               
               
                 2253 
                 0.564 ± 0.043 
                 0.646 ± 0.144 
                 2347 
                 0.530 ± 0.040 
                 0.753 ± 0.092 
               
               
                 2254 
                 0.641 ± 0.054 
                 0.756 ± 0.080 
                 2348 
                 0.454 ± 0.096 
                 0.840 ± 0.270 
               
               
                 2255 
                 0.721 ± 0.055 
                 0.653 ± 0.130 
                 2349 
                 0.504 ± 0.062 
                 0.674 ± 0.172 
               
               
                 2256 
                 0.765 ± 0.124 
                 0.796 ± 0.028 
                 2350 
                 0.678 ± 0.105 
                 0.755 ± 0.085 
               
               
                 2257 
                 0.802 ± 0.044 
                 0.647 ± 0.127 
                 2351 
                 1.306 ± 0.216 
                 1.216 ± 0.415 
               
               
                 2258 
                 0.972 ± 0.168 
                 0.882 ± 0.098 
                 2352 
                 0.749 ± 0.049 
                 1.012 ± 0.048 
               
               
                 2259 
                 0.836 ± 0.110 
                 0.743 ± 0.086 
                 2353 
                 0.324 ± 0.075 
                 0.635 ± 0.156 
               
               
                 2260 
                 1.030 ± 0.187 
                 0.861 ± 0.031 
                 2354 
                 0.741 ± 0.189 
                 1.043 ± 0.239 
               
               
                 2261 
                 0.657 ± 0.067 
                 0.568 ± 0.065 
                 2355 
                 0.248 ± 0.063 
                 0.457 ± 0.066 
               
               
                 2262 
                 0.277 ± 0.071 
                 0.755 ± 0.031 
                 2356 
                 0.210 ± 0.023 
                 0.574 ± 0.006 
               
               
                 2263 
                 0.875 ± 0.059 
                 1.126 ± 0.083 
                 2357 
                 0.435 ± 0.062 
                 0.737 ± 0.082 
               
               
                 2264 
                 0.183 ± 0.019 
                 0.381 ± 0.023 
                 2358 
                 0.731 ± 0.123 
                 0.647 ± 0.113 
               
               
                 2265 
                 0.186 ± 0.045 
                 0.448 ± 0.042 
                 2359 
                 0.354 ± 0.022 
                 0.576 ± 0.208 
               
               
                 2266 
                 0.368 ± 0.046 
                 0.808 ± 0.062 
                 2360 
                 0.962 ± 0.167 
                 1.102 ± 0.119 
               
               
                 2267 
                 0.651 ± 0.049 
                 1.029 ± 0.104 
                 2361 
                 0.603 ± 0.133 
                 0.800 ± 0.198 
               
               
                 2268 
                 0.210 ± 0.037 
                 0.409 ± 0.023 
                 2362 
                 0.454 ± 0.069 
                 0.673 ± 0.089 
               
               
                 2269 
                 0.302 ± 0.080 
                 0.530 ± 0.097 
                 2363 
                 0.452 ± 0.091 
                 0.653 ± 0.199 
               
               
                 2270 
                 0.613 ± 0.147 
                 0.658 ± 0.149 
                 2364 
                 0.855 ± 0.282 
                 1.070 ± 0.042 
               
               
                 2271 
                 0.930 ± 0.094 
                 1.056 ± 0.291 
                 2365 
                 1.259 ± 0.247 
                 1.132 ± 0.107 
               
               
                 2272 
                 0.864 ± 0.197 
                 1.028 ± 0.281 
                 2366 
                 0.695 ± 0.115 
                 0.879 ± 0.223 
               
               
                 2273 
                 0.588 ± 0.057 
                 0.574 ± 0.033 
                 2367 
                 0.376 ± 0.039 
                 0.665 ± 0.064 
               
               
                 2274 
                 0.506 ± 0.074 
                 0.870 ± 0.108 
                 2368 
                 1.140 ± 0.221 
                 1.036 ± 0.063 
               
               
                 2275 
                 0.464 ± 0.048 
                 0.515 ± 0.264 
                 2369 
                 0.338 ± 0.055 
                 0.464 ± 0.032 
               
               
                 2276 
                 0.330 ± 0.080 
                 0.543 ± 0.029 
                 2370 
                 0.294 ± 0.026 
                 0.498 ± 0.128 
               
               
                 2277 
                 0.702 ± 0.091 
                 0.625 ± 0.384 
                 2371 
                 0.166 ± 0.037 
                 0.193 ± 0.030 
               
               
                 2278 
                 0.564 ± 0.070 
                 0.947 ± 0.044 
                 2372 
                 0.514 ± 0.044 
                 0.831 ± 0.103 
               
               
                 2279 
                 0.280 ± 0.042 
                 0.506 ± 0.086 
                 2373 
                 0.162 ± 0.032 
                 0.369 ± 0.082 
               
               
                 2280 
                 0.911 ± 0.086 
                 0.871 ± 0.147 
                 2374 
                 0.192 ± 0.014 
                 0.355 ± 0.020 
               
               
                 2281 
                 0.651 ± 0.041 
                 0.914 ± 0.177 
                 2375 
                 0.305 ± 0.040 
                 0.481 ± 0.062 
               
               
                 2282 
                 0.824 ± 0.155 
                 1.209 ± 0.132 
                 2376 
                 0.228 ± 0.029 
                 0.546 ± 0.115 
               
               
                 2283 
                 0.882 ± 0.026 
                 1.175 ± 0.194 
                 2377 
                 0.958 ± 0.189 
                 0.900 ± 0.189 
               
               
                 2284 
                 0.787 ± 0.062 
                 1.227 ± 0.266 
                 2378 
                 0.734 ± 0.170 
                 0.994 ± 0.246 
               
               
                 2285 
                 0.723 ± 0.088 
                 1.109 ± 0.247 
                 2379 
                 0.939 ± 0.204 
                 0.858 ± 0.098 
               
               
                 2286 
                 0.878 ± 0.078 
                 1.291 ± 0.367 
                 2380 
                 1.722 ± 0.101 
                 1.128 ± 0.285 
               
               
                 2287 
                 0.751 ± 0.011 
                 0.871 ± 0.102 
                 2381 
                 1.063 ± 0.191 
                 0.756 ± 0.109 
               
               
                 2288 
                 0.932 ± 0.118 
                 0.943 ± 0.029 
                 2382 
                 1.151 ± 0.365 
                 1.070 ± 0.064 
               
               
                 2289 
                 1.039 ± 0.146 
                 0.992 ± 0.153 
                 2383 
                 1.060 ± 0.292 
                 0.833 ± 0.082 
               
               
                 2290 
                 0.353 ± 0.036 
                 0.698 ± 0.155 
                 2384 
                 0.439 ± 0.101 
                 0.533 ± 0.067 
               
               
                 2291 
                 0.434 ± 0.046 
                 0.911 ± 0.092 
                 2385 
                 0.515 ± 0.089 
                 0.701 ± 0.178 
               
               
                 2292 
                 0.832 ± 0.000 
                 1.135 ± 0.048 
                 2386 
                 0.274 ± 0.087 
                 0.603 ± 0.032 
               
               
                 2293 
                 0.925 ± 0.126 
                 1.010 ± 0.045 
                 2387 
                 0.201 ± 0.063 
                 0.436 ± 0.028 
               
               
                 2294 
                 0.546 ± 0.033 
                 0.743 ± 0.100 
                 2388 
                 0.436 ± 0.021 
                 0.901 ± 0.318 
               
               
                 2295 
                 0.863 ± 0.122 
                 1.047 ± 0.184 
                 2389 
                 0.820 ± 0.184 
                 1.085 ± 0.307 
               
               
                 2296 
                 0.213 ± 0.028 
                 0.411 ± 0.079 
                 2390 
                 0.568 ± 0.108 
                 0.772 ± 0.175 
               
               
                 2297 
                 0.643 ± 0.028 
                 0.704 ± 0.083 
                 2391 
                 0.129 ± 0.015 
                 0.273 ± 0.006 
               
               
                 2298 
                 0.695 ± 0.037 
                 0.729 ± 0.092 
                 2392 
                 0.283 ± 0.052 
                 0.636 ± 0.039 
               
               
                 2299 
                 0.827 ± 0.067 
                 0.907 ± 0.171 
                 2393 
                 1.049 ± 0.089 
                 0.862 ± 0.388 
               
               
                 2300 
                 0.786 ± 0.181 
                 1.090 ± 0.106 
                 2394 
                 0.254 ± 0.026 
                 0.533 ± 0.076 
               
               
                 2301 
                 0.423 ± 0.102 
                 0.558 ± 0.034 
                 2395 
                 0.218 ± 0.029 
                 0.494 ± 0.104 
               
               
                 2302 
                 0.147 ± 0.028 
                 0.414 ± 0.019 
                 2396 
                 0.939 ± 0.299  
                 1.321 ± 0.070 
               
               
                 2303 
                 0.294 ± 0.034 
                 0.414 ± 0.002 
                 2397 
                 0.119 ± 0.024 
                 0.254 ± 0.048 
               
               
                 2304 
                 0.302 ± 0.025 
                 0.528 ± 0.116 
                 2398 
                 0.534 ± 0.043 
                 1.047 ± 0.047 
               
               
                 2305 
                 0.992 ± 0.217 
                 0.961 ± 0.120 
                 2399 
                 0.418 ± 0.081 
                 0.784 ± 0.071 
               
               
                 2306 
                 0.613 ± 0.031 
                 0.596 ± 0.038 
                 2400 
                 0.165 ± 0.020 
                 0.478 ± 0.028 
               
               
                 2307 
                 0.702 ± 0.142 
                 0.800 ± 0.248 
                 2401 
                 0.174 ± 0.003 
                 0.375 ± 0.062 
               
               
                 2308 
                 0.998 ± 0.059 
                 0.799 ± 0.084 
                 2402 
                 0.128 ± 0.015 
                 0.389 ± 0.060 
               
               
                 2309 
                 1.081 ± 0.135 
                 0.823 ± 0.096 
                 2403 
                 0.568 ± 0.106 
                 0.930 ± 0.132 
               
               
                 2310 
                 0.923 ± 0.101 
                 0.785 ± 0.122 
                 2404 
                 0.104 ± 0.019 
                 0.234 ± 0.045 
               
               
                 2311 
                 0.841 ± 0.130 
                 0.888 ± 0.051 
                 2405 
                 0.138 ± 0.035 
                 0.261 ± 0.044 
               
               
                 2312 
                 0.725 ± 0.173 
                 0.899 ± 0.124 
                 2406 
                 0.168 ± 0.044 
                 0.241 ± 0.022 
               
               
                 2313 
                 0.886 ± 0.243 
                 0.853 ± 0.133 
                 2407 
                 0.124 ± 0.021 
                 0.222 ± 0.027 
               
               
                 2314 
                 0.920 ± 0.150 
                 0.692 ± 0.141 
                 2408 
                 0.282 ± 0.004 
                 0.730 ± 0.045 
               
               
                 2315 
                 0.876 ± 0.099  
                 0.781 ± 0.206 
                 2409 
                 0.104 ± 0.020 
                 0.301 ± 0.085 
               
               
                 2316 
                 0.579 ± 0.055 
                 0.797 ± 0.211 
                 2410 
                 0.154 ± 0.022 
                 0.228 ± 0.033 
               
               
                 2317 
                 0.843 ± 0.157 
                 0.842 ± 0.239 
                 2411 
                 0.410 ± 0.083 
                 0.796 ± 0.110 
               
               
                 2318 
                 0.780 ± 0.103 
                 0.885 ± 0.370 
                 2412 
                 0.291 ± 0.014 
                 0.515 ± 0.037 
               
               
                 2319 
                 0.234 ± 0.055 
                 0.454 ± 0.101 
                 2413 
                 0.317 ± 0.055 
                 0.675 ± 0.104 
               
               
                 2320 
                 0.486 ± 0.059 
                 0.770 ± 0.312 
                 2414 
                 0.167 ± 0.038 
                 0.422 ± 0.070 
               
               
                 2321 
                 0.665 ± 0.033 
                 0.561 ± 0.043 
                 2415 
                 0.119 ± 0.015 
                 0.180 ± 0.097 
               
               
                 2322 
                 0.306 ± 0.059 
                 0.468 ± 0.012 
                 2416 
                 0.166 ± 0.031 
                 0.247 ± 0.031 
               
               
                 2323 
                 0.664 ± 0.166 
                 0.631 ± 0.085 
                 2417 
                 0.253 ± 0.037 
                 0.295 ± 0.057 
               
               
                 2324 
                 1.046 ± 0.208 
                 1.081 ± 0.293 
               
               
                   
               
            
           
         
       
     
     Example 11. Hif2α RNAi Trigger EC 50  Determination 
     The eight best canonical sequences were further evaluated by determining the EC 50  concentration. Each trigger was assessed for knockdown under the same conditions and assays as above, but at 10 different concentrations ranging from 0.00051 nM to 10 nM. EC 50  were determined using GraphPad Prism software. Each of the top five canonical sequences were modified to contain UNA at sites 6 and 7. These triggers, along with their parent canonical sequences, were evaluated side-by-side for EC 50  concentration determination using the same conditions and assays as above, Table 6. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 EC 50  values (nM) determined in vitro for the indicated RNAi triggers. 
               
            
           
           
               
               
            
               
                 EC50 
                 EC50 UNAs 
               
            
           
           
               
               
               
               
               
            
               
                 ID number 
                 EC50 (nM) 
                 ID number 
                 Mod. 
                 EC50 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 XD-02335 
                 0.0593 
                 AD00988 
                 UNA6 
                 0.8406 
               
               
                   
                   
                 AD00993 
                 UNA7 
                 0.5504 
               
               
                 XD-02337 
                 0.1010 
                   
                   
                   
               
               
                 XD-02371 
                 0.0592 
                 AD00989 
                 UNA6 
                 0.3754 
               
               
                   
                   
                 AD00994 
                 UNA7 
                 0.08068 
               
               
                 XD-02391 
                 0.1554 
                   
                   
                   
               
               
                 XD-02397 
                 0.0858 
                   
                   
                   
               
               
                 XD-02404 
                 0.0570 
                 AD00990 
                 UNA6 
                 0.1534 
               
               
                   
                   
                 AD00995 
                 UNA7 
                 0.1689 
               
               
                 XD-02407 
                 0.0287 
                 AD00991 
                 UNA6 
                 0.3503 
               
               
                   
                   
                 AD00996 
                 UNA7 
                 0.1176 
               
               
                 XD-02415 
                 0.0892 
                 AD00992 
                 UNA6 
                 0.1419 
               
               
                   
                   
                 AD00997 
                 UNA7 
                 0.1827 
               
               
                   
               
            
           
         
       
     
     Example 12. Creation of SEAP-Expressing Clear Cell Renal Cell Carcinoma (ccRCC) A498 Cells 
     A pCR3.1 expression vector expressing the reporter gene secreted alkaline phosphatase (SEAP) under the CMV promoter was prepared by directional cloning of the SEAP coding sequence PCR amplified from Clontech&#39;s pSEAP2-basic vector. Convenient restriction sites were added onto primers used to amplify the SEAP coding sequence for cloning into the pCR3.1 vector (Invitrogen). The resultant construct pCR3-SEAP was used to create a SEAP-expressing A498 ccRCC cell line. Briefly, pCR3-SEAP plasmid was transfected into A498 ccRCC cells by electroporation following manufacturer&#39;s recommendation. Stable transfectants were selected by G418 resistance. Selected A498-SEAP clones were evaluated for SEAP expression and integration stability. 
     Example 13. Orthotopic RCC Tumor Bearing Mice with A498 Cell Stably Expressing SEAP 
     Female athymic nude mice were anesthetized with ˜3% isoflourane and placed in the right lateral decubitus position. A small, 0.5-1 cm, longitudinally abdominal incision in the left flank was made. Using a moist cotton swab, the left kidney was lifted out of the peritoneum and gently stabilized. Just before injection, a 1.0 ml syringe was filled with the cell/Matrigel mixture and a 27 gauge needle catheter was attached to the syringe tip. The filled syringe was then attached to a syringe pump (Harvard Apparatus, model PHD2000) and primed to remove air. The tip of a 27-gauge needle catheter attached to a syringe was inserted just below the renal capsule near the caudal pole and the tip of the needle was then carefully advanced cranially along the capsule 3-4 mm. A 10 μl aliquot of 2:1 (vol:vol) cell/matrigel mixture containing about 300,000 cells was slowly injected into the kidney parenchyma using a syringe pump. The needle was left in the kidney for 15-20 seconds to ensure the injection was complete. The needle was then removed from the kidney and a cotton swab was placed over the injection site for 30 seconds to prevent leakage of the cells or bleeding. The kidney was then gently placed back into the abdomen and the abdominal wall was closed. Serum was collected every 7-14 days after implantation to monitor tumor growth using a commercial SEAP assay kit. For most studies, tumor mice were used 5-6 weeks after implantation, when tumor measurements were typically around 4-8 mm. 
     Example 14. Evaluation of HiF2α-RNAi Triggers in Orthotopic RCC Tumor Bearing Mice 
     RGD targeted HiF2α-RNAi trigger delivery conjugates. Delivery polymers were modified using RGD-PEG-HyNic, RGD-PEG-ACit-PNP, or RDG-PEG-FCitFP-TFP and PEG-dipeptide modifying agents. The indicated amount of polymer 126 or 100A polymer was modified with 8×PEG 12 -ACit-PABC-PNP/0.5× aldehyde-PEG 24 -FCit-PABC-PNP (with RGD mimic #1-PEG-HyNic using protocol #1) and the indicated amount of the indicated Hif2α RNAi trigger. 
     Polymer 064 was modified according to protocol 7. Kidney RCC tumor-bearing mice were generated as described and treated with a single tail vein injection of isotonic glucose (G1) or the indicated Hif2α RNAi trigger-delivery polymer conjugate. Mice were euthanized at the indicated time after injection and total RNA was prepared from kidney tumor using Trizol reagent following manufacturer&#39;s recommendation. Relative HiF2α mRNA levels were determined by RT-qPCR as described below and compared to mice treated with delivery buffer (isotonic glucose) only. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Hif2α knockdown in mice following Hif2α RNAi trigger delivery.  
               
               
                 RNAi triggers were conjugated to the 
               
               
                 indicated reversibly modified delivery polymer. 
               
            
           
           
               
               
               
               
            
               
                 RNAi trigger 
                   
                   
                 Relative Expression 
               
            
           
           
               
               
               
               
               
            
               
                 duplex  
                   
                 Polymer 
                 day 
                 low error/ 
               
            
           
           
               
               
               
               
               
               
            
               
                 number 
                 μg 
                 number 
                 μg 
                 4 
                 high error 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 isotonic glucose 
                 0 
                   
                 0 
                 1.00 
                 0.06/0.06 
               
               
                 AD01031 
                 80 
                 126 
                 400 
                 0.20 
                 0.04/0.05 
               
               
                 AD01214 
                 80 
                 126 
                 400 
                 0.29 
                 0.08/0.12 
               
               
                 AD01214 
                 112.5 
                 006 
                 300 
                 0.36 
                 0.07/0.09 
               
               
                 AD01255 
                 80 
                 126 
                 400 
                 0.28 
                 0.05/0.05 
               
               
                 AD01476 
                 115 
                 100A 
                 375 
                 0.32 
                 0.04/0.04 
               
               
                 AD01291 
                 80 
                 126 
                 400 
                 0.19 
                 0.03/0.03 
               
               
                 AD01292 
                 80 
                 126 
                 400 
                 0.27 
                 0.06/0.08 
               
               
                 AD01293 
                 80 
                 126 
                 400 
                 0.20 
                 0.01/0.01 
               
               
                 AD01294 
                 80 
                 126 
                 400 
                 0.17 
                 0.01/0.02 
               
               
                 AD01295 
                 80 
                 126 
                 400 
                 0.22 
                 0.02/0.02 
               
               
                 AD01296 
                 80 
                 126 
                 400 
                 0.21 
                 0.04/0.06 
               
               
                 AD01029 
                 80 
                 126 
                 400 
                 0.94 
                 0.08/0.09 
               
               
                 AD01030 
                 80 
                 126 
                 400 
                 0.47 
                 0.08/0.10 
               
               
                 AD01256 
                 80 
                 126 
                 400 
                 0.22 
                 0.05/0.07 
               
               
                 AD01257 
                 80 
                 126 
                 400 
                 0.24 
                 0.04/0.05 
               
               
                 AD01258 
                 80 
                 126 
                 400 
                 0.38 
                 0.03/0.03 
               
               
                 AD01424 
                 150 
                 100A 
                 300 
                 0.54 
                 0.06/0.07 
               
               
                 AD01404 
                 150 
                 100A 
                 300 
                 0.58 
                 0.11/0.13 
               
               
                 AD01405 
                 150 
                 100A 
                 300 
                 0.51 
                 0.10/0.12 
               
               
                 AD01406 
                 150 
                 100A 
                 300 
                 0.45 
                 0.06/0.07 
               
               
                 AD01407 
                 150 
                 100A 
                 300 
                 0.47 
                 0.06/0.07 
               
               
                 AD01408 
                 150 
                 100A 
                 300 
                 0.50 
                 0.07/0.09 
               
               
                 AD01409 
                 150 
                 100A 
                 300 
                 0.55 
                 0.03/0.03 
               
               
                 AD01410 
                 150 
                 100A 
                 300 
                 0.41 
                 0.10/0.12 
               
               
                 AD01411 
                 150 
                 100A 
                 300 
                 0.36 
                 0.01/0.01 
               
               
                 AD01288 
                 115 
                 100A 
                 375 
                 0.32 
                 0.02/0.02 
               
               
                 AD01522 
                 115 
                 100A 
                 375 
                 0.44 
                 0.07/0.09 
               
               
                 AD01289 
                 115 
                 100A 
                 375 
                 0.28 
                 0.06/0.08 
               
               
                 AD01290 
                 115 
                 100A 
                 375 
                 0.39 
                 0.02/0.02 
               
               
                 AD01523 
                 115 
                 100A 
                 375 
                 0.49 
                 0.04/0.05 
               
               
                 AD01524 
                 115 
                 100A 
                 375 
                 0.26 
                 0.05/0.07 
               
               
                 AD01554 
                 115 
                 100A 
                 375 
                 0.29 
                 0.04/0.04 
               
               
                 AD01555 
                 115 
                 100A 
                 375 
                 0.20 
                 0.03/0.03 
               
               
                 AD01025 
                 80 
                 126 
                 400 
                 0.34 
                 0.02/0.02 
               
               
                 AD01023 
                 80 
                 126 
                 400 
                 0.93 
                 0.10/0.12 
               
               
                 AD01024 
                 80 
                 126 
                 400 
                 0.51 
                 0.04/0.05 
               
               
                 AD01028 
                 80 
                 126 
                 400 
                 0.39 
                 0.04/0.04 
               
               
                 AD01026 
                 80 
                 126 
                 400 
                 0.97 
                 0.12/0.13 
               
               
                 AD01027 
                 80 
                 126 
                 400 
                 0.92 
                 0.08/0.09 
               
               
                 AD01034 
                 80 
                 126 
                 400 
                 0.35 
                 0.07/0.09 
               
               
                 AD01032 
                 80 
                 126 
                 400 
                 1.00 
                 0.09/0.10 
               
               
                 AD01033 
                 80 
                 126 
                 400 
                 1.08 
                 0.08/0.09 
               
               
                 AD01022 
                 80 
                 126 
                 400 
                 0.53 
                 0.07/0.09 
               
               
                 AD01020 
                 80 
                 126 
                 400 
                 0.94 
                 0.06/0.06 
               
               
                 AD01021 
                 80 
                 126 
                 400 
                 0.90 
                 0.05/0.05 
               
               
                 AD01654 
                 100 
                 100A 
                 250 
                 0.185 
                 0.01/0.01 
               
               
                 AD01655 
                 100 
                 100A 
                 250 
                 0.234 
                 0.02/0.02 
               
               
                 AD01656 
                 100 
                 100A 
                 250 
                 0.184 
                 0.01/0.01 
               
               
                 AD01657 
                 100 
                 100A 
                 250 
                 0.256 
                 0.03/0.03 
               
               
                 AD01658 
                 100 
                 100A 
                 250 
                 0.138 
                 0.01/0.01 
               
               
                 AD01659 
                 100 
                 100A 
                 250 
                 0.249 
                 0.04/0.05 
               
               
                 AD01884 
                 100 
                 064 
                 250 
                 0.091 
                 0.01/0.01 
               
               
                 AD01885 
                 100 
                 064 
                 250 
                 0.146 
                 0.02/0.02 
               
               
                 AD01886 
                 100 
                 064 
                 250 
                 0.292 
                 0.04/0.05 
               
               
                 AD01887 
                 100 
                 064 
                 250 
                 0.329 
                 0.05/0.06 
               
               
                 AD01888 
                 100 
                 064 
                 250 
                 0.209 
                 0.04/0.08 
               
               
                 AD01889 
                 100 
                 064 
                 250 
                 0.282 
                 0.04/0.05 
               
               
                 AD01890 
                 100 
                 064 
                 250 
                 0.256 
                 0.02/0.03 
               
               
                 AD01891 
                 100 
                 064 
                 250 
                 0.189 
                 0.02/0.03 
               
               
                 AD01892 
                 100 
                 064 
                 250 
                 0.146 
                 0.03/0.03 
               
               
                 AD01893 
                 100 
                 064 
                 250 
                 0.115 
                 0.02/0.03 
               
               
                 AD02691 
                 75 
                 064 
                 187.5 
                 0.124 
                 0.04/0.07 
               
               
                 AD02692 
                 75 
                 064 
                 187.5 
                 0.089 
                 0.03/0.04 
               
               
                 AD02693 
                 75 
                 064 
                 187.5 
                 0.122 
                 0.01/0.01 
               
               
                 AD02694 
                 75 
                 064 
                 187.5 
                 0.099 
                 0.01/0.01 
               
               
                 AD02695 
                 75 
                 064 
                 187.5 
                 0.101 
                 0.02/0.02 
               
               
                 AD02733 
                 75 
                 064 
                 187.5 
                 0.283 
                 0.02/0.03 
               
               
                 AD02734 
                 75 
                 064 
                 187.5 
                 0.262 
                 0.03/0.03 
               
               
                 AD02735 
                 75 
                 064 
                 187.5 
                 0.080 
                 0.01/0.02 
               
               
                 AD01884 
                 75 
                 064 
                 187.5 
                 0.227 
                 0.02/0.02 
               
               
                 AD01884 
                 50 
                 064 
                 125 
                 0.203 
                 0.03/0.03 
               
               
                 AD02692 
                 75 
                 064 
                 187.5 
                 0.121 
                 0.02/0.02 
               
               
                 AD02692 
                 50 
                 064 
                 125 
                 0.092 
                 0.01/0.01 
               
               
                 AD02695 
                 75 
                 064 
                 187.5 
                 0.155 
                 0.02/0.02 
               
               
                 AD02695 
                 50 
                 064 
                 125 
                 0.123 
                 0.03/0.03 
               
               
                 AD02735 
                 75 
                 064 
                 187.5 
                 0.222 
                 0.07/0.10 
               
               
                 AD02735 
                 50 
                 064 
                 125 
                 0.144 
                 0.03/0.03 
               
               
                 AD02857 
                 50 
                 064 
                 125 
                 0.192 
                 0.03/0.03 
               
               
                 AD02858 
                 50 
                 064 
                 125 
                 0.192 
                 0.04/0.05 
               
               
                 AD02859 
                 50 
                 064 
                 125 
                 0.214 
                 0.03/0.03 
               
               
                 AD02860 
                 50 
                 064 
                 125 
                 0.165 
                 0.02/0.02 
               
               
                 AD02949 
                 50 
                 064 
                 125 
                 0.176 
                 0.05/0.07 
               
               
                 AD02074 
                 50 
                 064 
                 125 
                 0.566 
                 0.01/0.13 
               
               
                 AD02861 
                 50 
                 064 
                 125 
                 0.103 
                 0.03/0.05 
               
               
                 AD02862 
                 50 
                 064 
                 125 
                 0.093 
                 0.05/0.11 
               
               
                 AD02873 
                 50 
                 064 
                 125 
                 0.079 
                 0.04/0.06 
               
               
                 AD02875 
                 50 
                 064 
                 125 
                 0.101 
                 0.01/0.02 
               
               
                 AD03011 
                 50 
                 064 
                 125 
                 0.183 
                 0.01/0.02 
               
               
                 AD02874 
                 50 
                 064 
                 125 
                 0.138 
                 0.05/0.07 
               
               
                 AD03187 
                 50 
                 064 
                 125 
                 1.000 
                 0.06/0.07 
               
               
                 AD03188 
                 50 
                 064 
                 125 
                 0.308 
                 0.08/0.07 
               
               
                 AD03189 
                 50 
                 064 
                 125 
                 0.245 
                 0.02/0.02 
               
               
                 AD03190 
                 50 
                 064 
                 125 
                 0.269 
                 0.08/0.12 
               
               
                 AD03191 
                 50 
                 064 
                 125 
                 0.307 
                 0.13/0.24 
               
               
                 AD03192 
                 50 
                 064 
                 125 
                 0.286 
                 0.01/0.01 
               
               
                 AD03193 
                 50 
                 064 
                 125 
                 0.275 
                 0.07/0.09 
               
               
                 AD03125 
                 50 
                 064 
                 125 
                 0.205 
                 0.04/0.05 
               
               
                 AD03126 
                 50 
                 064 
                 125 
                 0.172 
                 0.04/0.04 
               
               
                 AD03253 
                 50 
                 064 
                 125 
                 0.188 
                 0.04/0.05 
               
               
                 AD03264 
                 50 
                 064 
                 125 
                 0.264 
                 0.09/0.13 
               
               
                 AD03265 
                 50 
                 064 
                 125 
                 0.294 
                 0.07/0.08 
               
               
                 AD03266 
                 50 
                 064 
                 125 
                 0.408 
                 0.07/0.08 
               
               
                 AD03254 
                 50 
                 064 
                 125 
                 0.295 
                 0.06/0.07 
               
               
                 AD03255 
                 50 
                 064 
                 125 
                 0.264 
                 0.07/0.10 
               
               
                 AD03256 
                 50 
                 064 
                 125 
                 0.333 
                 0.06/0.08 
               
               
                 AD03257 
                 50 
                 064 
                 125 
                 0.203 
                 0.04/0.05 
               
               
                 AD03258 
                 50 
                 064 
                 125 
                 0.137 
                 0.02/0.02 
               
               
                 AD03259 
                 50 
                 064 
                 125 
                 0.179 
                 0.03/0.04 
               
               
                 AD03260 
                 50 
                 064 
                 125 
                 0.175 
                 0.03/0.04 
               
               
                 AD03261 
                 50 
                 064 
                 125 
                 0.177 
                 0.02/0.02 
               
               
                 AD03262 
                 50 
                 064 
                 125 
                 0.197 
                 0.01/0.01 
               
               
                 AD03263 
                 50 
                 064 
                 125 
                 0.134 
                 0.04/0.06 
               
               
                   
               
            
           
         
       
     
     Quantitative Real-Time PCR assay. In preparation for quantitative PCR, total RNA was isolated from tissue samples homogenized in TrReagent (Molecular Research Center, Cincinnati, Ohio) following the manufacturers protocol. Approximately 500 ng RNA was reverse-transcribed using the High Capacity cDNA Reverse Transcription Kit (Life Technologies). For human (tumor) Hif2α (EPAS 1) expression, pre-manufactured TaqMan gene expression assays for human Hif2α (Catalog #4331182) and CycA (PPIA) Catalog #: 4326316E) were used in biplex reactions in triplicate using TaMan Gene Expression Master Mix (Life Technologies) or VeriQuest Probe Master Mix (Affymetrix). For human (tumor) VegFa (VEGFA) expression, pre-manufactured TaqMan gene expression assays for human VegFa (Catalog #4331182, Assay ID: Hs00900055) and CycA (Part #: 4326316E) were used in biplex reactions in triplicate using TaqMan Gene Expression Master Mix (Life Technologies) or VeriQuest Probe Master Mix (Affymetrix). Quantitative PCR was performed by using a 7500 Fast or StepOnePlus Real-Time PCR system (Life Technologies). The AACT method was used to calculate relative gene expression. 
     Example 15. Multi-Dose Hif2α RNAi Trigger-Delivery Polymer Conjugate Inhibits Tumor Growth in Orthotopic RCC Tumor Bearing Mice 
     Hif2α RNAi trigger-delivery polymer conjugate was prepared using protocol #1 with RNAi trigger duplex ID AD01031 and polymer Ant 126. The conjugate was then TFF purified and polymer concentration, RNAi trigger, RGD and modifying conjugation efficiency was determined as described above. Weekly doses of Hif2α RNAi trigger-delivery polymer conjugate containing either 400 μg (polymer weight) or 280 μg (polymer weight) were administered intravenously to 2 different groups of tumor bearing mice. Tumor bearing mice receiving isotonic glucose (IG) were used as treatment control. A total of 3 weekly doses were administered during the course of study. Tumor growth rates were evaluated by serum SEAP collected at 5-7 days interval during treatment. Tumor weight and volume was determined at necropsy. Gross tumor morphology and H&amp;E histopathology were evaluated. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Hif2α RNAi trigger-delivery polymer conjugate  
               
               
                 knockdown HiF2α and VEGFa 
               
            
           
           
               
               
               
            
               
                   
                 Hif2α expression 
                 VEGFa expression 
               
            
           
           
               
               
               
               
               
            
               
                 Treat- 
                 Relative 
                 low/high 
                 Relative 
                 low/high 
               
               
                 ment 
                 Expression 
                 error 
                 Expression 
                 error 
               
               
                   
               
               
                 G1-IG 
                 1.00 
                 0.07/0.07 
                 1.00 
                 0.07/0.08 
               
               
                 G2-400 μg 
                 0.18 
                 0.03/0.04 
                 0.45 
                 0.07/0.09 
               
               
                 G3-280 μg 
                 0.19 
                 0.04/0.05 
                 0.39 
                 0.10/0.13 
               
               
                   
               
            
           
         
       
     
     Expression of Hif2α in the 400 μg or 280 μg Hif2α RNAi trigger-delivery polymer conjugate group was 82% and 81% decreased, respectively, compared to control treatment (Table 8). Expression of VEGFa, a well characterized down-stream Hif2α regulated gene, was also decreased by 55% and 61%, respectively (Table 8). 
     Collectively, after 3 weekly Hif2α RNAi trigger-delivery polymer conjugate injections, tumor growth was dramatically inhibited in both dosages evaluated. This is supported by the overall tumor sizes and serum SEAP levels ( FIGS. 8-9 and 12 , Table 9). A downward trend of the SEAP levels after the third injections suggest beginning of tumor regression. In addition, tumor histopathology examination from H&amp;E stained formalin fixed paraffin sections showed destruction of typical RCC tubular structure. The number of apoptotic cells was increased in treatment groups. Some tumor sample contained large areas of tumor necrosis ( FIG. 10 ). 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Serum SEAP levels during treatment, G1 and G2, n = 4; G3, n = 3 
               
            
           
           
               
               
            
               
                   
                 SEAP (fold-changed relative to day −1) 
               
            
           
           
               
               
               
               
               
            
               
                 Treatment 
                 Day −1 
                 Day 7 
                 Day 14 
                 Day 21 
               
               
                   
               
               
                 G1-IG 
                 1.00 ± 0.19 
                 1.65 ± 0.22 
                 3.44 ± 0.23 
                 7.48 ± 0.27 
               
               
                 G2-400 μg 
                 1.00 ± 0.45 
                 0.79 ± 0.43 
                 1.36 ± 0.61 
                 1.25 ± 0.68 
               
               
                 G3-280 μg 
                 1.00 ± 0.14 
                 1.46 ± 0.09 
                 2.55 ± 0.29 
                 1.82 ± 0.35 
               
               
                   
               
            
           
         
       
     
     Example 16. Evaluation of HiF2α-RNAi triggers in orthotopic RCC tumor bearing mice. RGD targeted HiF2α-RNAi trigger delivery polymer conjugates were formed using polymer 126, 100A, or 006. The RNAi trigger, μg indicates the quantity of trigger reacted with polymer. The polymer was modified with the indicated RGD mimic and PEG modifying agents as described above. Kidney RCC tumor-bearing mice were generated as described and treated with a single tail vein injection of isotonic glucose (G1) or the indicated Hif2α RNAi trigger-delivery polymer conjugate. Mice were euthanized 72 h (day 4) after injection and total RNA was prepared from kidney tumor using Trizol reagent following manufacturer&#39;s recommendation. Relative HiF2α mRNA levels were determined by RT-qPCR as described and compared to mice treated with delivery buffer (isotonic glucose) only (Table 11). 
     Example 17. HiF2α RNAi Trigger/Second Therapeutic Combination Study 
     HiF2α RNAi trigger-delivery polymer conjugate (125 μg polymer) was prepared using protocol 7 Duplex ID No. AD1884 and polymer 064. HiF2α RNAi trigger-delivery polymer conjugate was dosed every 4 weeks by iv injection, 4 doses total. Sunitinib (Malate salt) obtained from LC laboratories was suspended in Ora-plus/Ora sweet (50:50, vol:vol). Sunitinib treatment started 2 weeks after the first HiF2α RNAi trigger dose was administered. Mice were dosed by oral gavage 5 days/week for 2 weeks, then off 2 weeks, 3 cycles total. 
     Tumor growth rates were evaluated by serum SEAP collected at 5-7 days interval during treatment. Tumor weight and volume was determined at necropsy. Gross tumor morphology and H&amp;E histopathology were evaluated. Relative HiF2a expression levels were of were 11.4%, 73.8%, and 77.6% decreased in the sunitinib alone, DPC+sunitinib and DPC alone treated groups, respectively (Table 10A). Combined HiF2a RNAi trigger and sunitinib treatments resulted in increased tumor growth inhibition response. Overall smaller tumor sizes were smaller and lower overall growth (as measured by overall-fold increase in SEAP) was observed (Table 10B). 
     
       
         
           
               
             
               
                 TABLE 10A 
               
             
            
               
                   
               
               
                 HiF2α expression in RCC tumors in animal models treated with  
               
               
                 Sunitinib, HiF2α RNAi trigger, or HiF2α RNAi trigger + Sunitinib. 
               
            
           
           
               
               
            
               
                   
                 HiF2α expression 
               
            
           
           
               
               
               
               
            
               
                 Treatment 
                 Relative expression 
                 Low error 
                 High error 
               
               
                   
               
               
                 isotonic glucose 
                 1.000 
                 0.153 
                 0.180 
               
               
                 Sunitinib 
                 0.886 
                 0.070 
                 0.076 
               
               
                 HiF2α RNAi trigger 
                 0.262 
                 0.071 
                 0.097 
               
               
                 HiF2α RNAi trigger + 
                 0.224 
                 0.081 
                 0.126 
               
               
                 Sunitinib 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 10B 
               
             
            
               
                   
               
               
                 Tumor size and SEAP expression in RCC tumors in animal models treated with 
               
               
                 Sunitinib, HiF2α RNAi trigger, or HiF2α RNAi trigger + Sunitinib. 
               
            
           
           
               
               
               
               
            
               
                 Treatment 
                 Tumor weight (mg) 
                 Tumor volume (mm3) 
                 Fold increase in SEAP 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 isotonic glucose 
                 4158.5 ± 865  
                 3576.3 ± 279 
                  21.8 ± 11 
               
               
                 Sunitinib 
                 2385.7 ± 845  
                 2113.5 ± 368 
                   18.1 ± 9.8 
               
               
                 HiF2α RNAi trigger 
                 2130.9 ± 1066 
                 1537.4 ± 999 
                 20.54 ± 20 
               
               
                 HiF2α RNAi trigger + 
                 1075.8 ± 600  
                 1008.8 ± 650 
                   5.7 ± 3.3 
               
               
                 Sunitinib 
                   
                   
                   
               
               
                   
               
            
           
         
       
     
     Other Embodiments: It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. 
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Hif2α expression in RCC cells in RCC tumor  
               
               
                 bearing mice following Hif2α RNAi trigger delivery. 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 HiF2α  
                 polymer 
                   
                   
                   
                   
                 Relative Expression 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 RNAi trigger 
                   
                   
                 purifi- 
                 RGD 
                 PEG 
                   
                 error 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 duplex ID 
                 μg 
                 ID 
                 μg 
                 cation 
                 modifying agent 
                 amt. 
                 no. 
                 modifying agent 
                 day 4 
                 low 
                 high 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 isotonic glucose 
                   
                   
                   
                   
                   
                   
                   
                 1.000 
                 0.060 
                 0.064 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 AD01031 
                 80 
                 126 
                 280 
                   
                 RGD-PEG 8 -HyNic 
                 0.5× 
                   
                 PEG 12 -ACit-PABC-PNP 
                 0.300 
                 0.074 
                 0.098 
               
               
                 AD01031 
                 80 
                 126 
                 280 
                   
                 RGD-PEG 8 -ACit- 
                 0.4× 
                   
                 PEG 6 -ACit-PABC-PNP 
                 0.311 
                 0.055 
                 0.067 
               
               
                   
                   
                   
                   
                   
                 PABC-PNP 
                   
                   
                   
                   
                   
                   
               
               
                 AD01214 
                 80 
                 126 
                 280 
                 TFF 
                 RGD-PEG 8 -HyNic 
                 0.5× 
                   
                 PEG 12 -FCit-PABC-PNP 
                 0.489 
                 0.022 
                 0.023 
               
               
                 AD01214 
                 80 
                 126 
                 280 
                   
                 RGD-PEG 8 -HyNic 
                 0.5× 
                   
                 PEG 12 -FCitFP-TFP 
                 0.210 
                 0.032 
                 0.038 
               
               
                 AD01214 
                 80 
                 126 
                 280 
                   
                 RGD-PEG 8 -ACit- 
                 0.4× 
                   
                 PEG 6 -ACit-PABC-PNP 
                 0.360 
                 0.019 
                 0.021 
               
               
                   
                   
                   
                   
                   
                 PABC-PNP 
                   
                   
                   
                   
                   
                   
               
               
                 AD01214 
                 80 
                 126 
                 280 
                   
                 RGD-PEG 8 -ACitFP-NHS 
                   1× 
                   
                 PEG 6 -ACit-PABC-PNP 
                 0.288 
                 0.005 
                 0.005 
               
               
                 AD01214 
                 115 
                 100A 
                 375 
                   
                 RGD-PEG 8 -HyNic 
                 0.5× 
                   
                 PEG 12 -FCitFP-TFP 
                 0.258 
                 0.033 
                 0.038 
               
               
                 AD01214 
                 112.5 
                 100A 
                 375 
                 TFF 
                 RGD-PEG 15 -FCitFP-TFP 
                 0.5× 
                 10.8 
                 PEG 12 -ACit-PABC-PNP 
                 0.193 
                 0.046 
                 0.061 
               
               
                 AD01214 
                 112.5 
                 100A 
                 375 
                 TFF 
                 RGD-PEG 15 -FCitFP-TFP 
                   1× 
                 16.1 
                 PEG 12 -ACit-PABC-PNP 
                 0.182 
                 0.007 
                 0.008 
               
               
                 AD01214 
                 112.5 
                 100A 
                 375 
                 TFF 
                 RGD-PEG 15 -FCitFP-TFP 
                   2× 
                 29.0 
                 PEG 12 -ACit-PABC-PNP 
                 0.182 
                 0.031 
                 0.038 
               
               
                 AD01214 
                 112.5 
                 100A 
                 375 
                 TFF 
                 RGD-PEG 19 -FCitFP-TFP 
                 0.5× 
                 10.7 
                 PEG 12 -ACit-PABC-PNP 
                 0.163 
                 0.023 
                 0.027 
               
               
                 AD01214 
                 112.5 
                 100A 
                 375 
                 TFF 
                 RGD-PEG 19 -FCitFP-TFP 
                   1× 
                 18.5 
                 PEG 12 -ACit-PABC-PNP 
                 0.114 
                 0.011 
                 0.012 
               
               
                 AD01214 
                 112.5 
                 100A 
                 375 
                 TFF 
                 RGD-PEG 19 -FCitFP-TFP 
                   2× 
                 31.1 
                 PEG 12 -ACit-PABC-PNP 
                 0.182 
                 0.047 
                 0.063 
               
               
                 AD01214 
                 112.5 
                 100A 
                 375 
                   
                 RGD-PEG 19 -FCitFP-TFP 
                   1× 
                   
                 PEG 12 -FCitFP-TFP 
                 0.148 
                 0.079  
                 0.169 
               
               
                 AD01214 
                 112.5 
                 100A 
                 375 
                   
                 RGD-PEG 19 -FCitFP-TFP 
                   1× 
                   
                 PEG 12 -FCitFP-TFP 
                 0.188 
                 0.026  
                 0.03 
               
               
                 AD01214 
                 112.5 
                 100A 
                 375 
                   
                 RGD-PEG 19 -FCitFP-TFP 
                   1× 
                   
                 PEG 12 -ACit-PABC-PNP 
                 0.195 
                 0.043 
                 0.055 
               
               
                 AD01214 
                 112.5 
                 006 
                 300 
                   
                 RGD-PEG 8 -HyNic 
                   
                   
                 PEG 12 -ACit-PABC-PNP 
                 0.357 
                 0.069 
                 0.086 
               
               
                 AD01214 
                 112.5 
                 100A 
                 375 
                 TFF 
                 RGD-PEG 20 -FCitFP-TFP 
                 0.125×  
                 1.9  
                 PEG 12 -ACit-PABC-PNP 
                 0.169 
                 0.052 
                 0.075 
               
               
                 AD01214 
                 112.5 
                 100A 
                 375 
                 TFF 
                 RGD-PEG 20 -FCitFP-TFP 
                 0.25×  
                 3.4  
                 PEG 12 -ACit-PABC-PNP 
                 0.168 
                 0.029 
                 0.035 
               
               
                 AD01214 
                 112.5 
                 100A 
                 375 
                 TFF 
                 RGD-PEG 20 -FCitFP-TFP 
                 0.5× 
                 6.6 
                 PEG 12 -ACit-PABC-PNP 
                 0.130 
                 0.004 
                 0.005 
               
               
                 AD01214 
                 112.5 
                 100A 
                 375 
                 TFF 
                 RGD-PEG 20 -FCitFP-TFP 
                   1× 
                 12.7 
                 PEG 12 -ACit-PABC-PNP 
                 0.121 
                 0.016 
                 0.018 
               
               
                 AD01214 
                 112.5 
                 100A 
                 375 
                 TFF 
                 RGD-PEG 20 -FCitFP-TFP 
                 1.5× 
                 20.3 
                 PEG 12 -ACit-PABC-PNP 
                 0.135 
                 0.018 
                 0.020