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Matched Legal Cases: ['art.\n1', 'Application No. 00914455', 'Application No. 00914455', 'Application No. 00914455', 'Application No. 00914455', 'Application No. 00914455', 'Application No. 00914455', 'Application No. 553987', 'Application No. 2007116168', 'Application No. 00914455', 'Application No. 0702035']

Patent US7910566 - Prevention and treatment of acute renal failure and other kidney diseases by ... - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign in<nobr>Advanced Patent Search</nobr>PatentsThe invention relates to a double-stranded compound, preferably an oligoribonucleotide, which down-regulates the expression of a human p53 gene. The invention also relates to a pharmaceutical composition comprising the compound, or a vector capable of expressing the oligoribonucleotide compound, and...http://www.google.com/patents/US7910566?utm_source=gb-gplus-sharePatent US7910566 - Prevention and treatment of acute renal failure and other kidney diseases by inhibition of p53 by siRNAAdvanced Patent SearchPublication numberUS7910566 B2Publication typeGrantApplication numberUS 12/006,722Publication dateMar 22, 2011Filing dateJan 4, 2008Priority dateMar 9, 2006Also published asUS20090105173Publication number006722, 12006722, US 7910566 B2, US 7910566B2, US-B2-7910566, US7910566 B2, US7910566B2InventorsElena FeinsteinOriginal AssigneeQuark Pharmaceuticals Inc.Export CitationBiBTeX, EndNote, RefManPatent Citations (36), Non-Patent Citations (102), Referenced by (7), Classifications (8), Legal Events (1) External Links: USPTO, USPTO Assignment, EspacenetPrevention and treatment of acute renal failure and other kidney diseases by inhibition of p53 by siRNAUS 7910566 B2Abstract The invention relates to a double-stranded compound, preferably an oligoribonucleotide, which down-regulates the expression of a human p53 gene. The invention also relates to a pharmaceutical composition comprising the compound, or a vector capable of expressing the oligoribonucleotide compound, and a pharmaceutically acceptable carrier. The present invention also contemplates a method of treating a patient suffering from acute renal failure or other kidney diseases comprising administering to the patient the pharmaceutical composition in a therapeutically effective dose so as to thereby treat the patient.
Thus, RNA interference (RNAi) refers to the process of sequence-specific post-transcriptional gene silencing in mammals mediated by small interfering RNAs (siRNAs) (Fire et al, 1998, Nature 391, 806) or microRNAs (miRNAs) (Ambros V. Nature 431:7006, 350-355(2004); and Bartel D P. Cell. 2004 Jan. 23; 116(2): 281-97 MicroRNAs: genomics, biogenesis, mechanism, and function). The corresponding process in plants is commonly referred to as specific post-transcriptional gene silencing or RNA silencing and is also referred to as quelling in fungi. An siRNA is a double-stranded RNA molecule which down-regulates or silences (prevents) the expression of a gene/mRNA of its endogenous counterpart. RNA interference is based on the ability of dsRNA species to enter a specific protein complex, where it is then targeted to the complementary cellular RNA and specifically degrades it. Thus, the RNA interference response features an endonuclease complex containing an siRNA, commonly referred to as an RNA-induced silencing complex (RISC), which mediates cleavage of single-stranded RNA having a sequence complementary to the antisense strand of the siRNA duplex. Cleavage of the target RNA may take place in the middle of the region complementary to the antisense strand of the siRNA duplex (Elbashir et al 2001, Genes Dev., 15, 188). In more detail, longer dsRNAs are digested into short (17-29 hp) dsRNA fragments (also referred to as short inhibitory RNAs��siRNAs�) by type III RNAses (DICER, DROSHA, etc., Bernstein et al., Nature, 2001, v. 409, p. 363-6; Lee et al., Nature, 2003, 425, p. 415-9). The RISC protein complex recognizes these fragments and complementary mRNA. The whole process is culminated by endonuclease cleavage of target mRNA (McManus&Sharp, Nature Rev Genet, 2002, v. 3, p. 737-47; Paddison &Hannon, Curr Opin Mol Ther. 2003 June; 5(3): 217-24). For information on these terms and proposed mechanisms, see Bernstein E., Denli A M. Hannon G J: 2001 The rest is silence. RNA. I; 7(11): 1509-21; Nishikura K.: 2001 A short primer on RNAi: RNA-directed RNA polymerase acts as a key catalyst. Cell. 116; 107(4): 415-8 and PCT publication WO 01/36646 (Glover et al).
Several studies have revealed that siRNA therapeutics are effective in vivo in both mammals and in humans. Bitko et al., have shown that specific siRNA molecules directed against the respiratory syncytial virus (RSV) nucleocapsid N gene are effective in treating mice when administered intranasally (Bitko et al., �Inhibition of respiratory viruses by nasally administered siRNA�, Nat. Med. 2005, 11(1):50-55). A review of the use of siRNA in medicine was recently published by Barik S. in J. Mol. Med. (2005) 83: 764-773). Furthermore, a phase I clinical study with short siRNA molecule that targets the VEGFR1 receptor for the treatment of Age-Related Macular Degeneration (AMD) has been conducted in human patients. The siRNA drug administered by an intravitreal inter-ocular injection was found effective and safe in 14 patients tested after a maximum of 157 days of follow up (Boston Globe Jan. 21, 2005).
SUMMARY OF THE INVENTION The present invention provides double stranded oligoribonucleotides that inhibit the p53 gene. The invention also provides a pharmaceutical composition comprising one or more such oligoribonucleotides, and a vector capable of expressing the oligoribonucleotide. The present invention also relates to methods and compositions for treating or preventing acute renal failure (ARF) following ischemic-reperfusion event, wherein the composition is administered in a therapeutically effective dose following the initiation of the ischemic-reperfusion event. The present invention also relates to methods and compositions for treating or preventing the incidence or severity of hearing impairment (or balance impairment), particularly hearing impairment associated with cell death of the inner ear hair cells or outer ear hair cells. The methods and compositions involve administering to a mammal in need of such treatment a prophylactically or therapeutically effective amount of one or more compounds which down-regulate expression of the p53 gene, particularly small interfering RNAs (siRNAs), small molecule inhibitors of p53 as described herein or antibodies to p53 polypeptide.
DETAILED DESCRIPTION OF THE INVENTION The present invention relates generally to compounds which down-regulate expression of the p53 gene, particularly to novel small interfering RNAs (siRNAs), and to the use of these novel siRNAs in the treatment of various diseases and medical conditions in particular various forms of acute renal failure or hearing impairment as described above. Preferred lists of such siRNA are in Tables A, B, C1 and C2.
As used herein, an �inhibitor� is a compound which is capable of inhibiting or reducing the expression or activity of a gene or the product of such gene to an extent sufficient to achieve a desired biological or physiological effect. The term �inhibitor� as used herein refers to one or more of an oligonucleotide inhibitor, including siRNA, shRNA, aptamers, antisense molecules, miRNA and ribozymes, as well as antibodies.
As used herein, the term �Oligonucleotide� refers to a sequence having from about 2 to about 50 linked nucleotides or linked modified nucleotides, or a combination of modified and unmodified nucleotide. Oligonucleotide includes the terms oligomer, antisense strand and sense strand.
�Nucleotide� is meant to encompass deoxyribonucleotides and ribonucleotides, which may be natural or synthetic, and or modified or unmodified. Modifications include changes to the sugar moiety, the base moiety and or the linkages between ribonucleotides in the oligoribonucleotide.
In some embodiments the compound comprises one or more ribonucleotides unmodified in their sugar residues. In other embodiments the compound comprises at least one ribonucleotide modified in the sugar residue. In some embodiments the compound comprises a modification at the 2′ position of the sugar residue. Modifications in the 2′ position of the sugar residue include amino, fluoro, methoxy, alkoxy and alkyl moieties. In certain preferred embodiments the modification comprises a ribonucleotide comprising a methoxy moiety at the 2′ position (2′-O-methyl; 2′-O-Me; 2′-O�CH3) of the sugar residue.
�Treatment� refers to both therapeutic treatment and prophylactic or preventative measures,
�Treatment� refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an apoptotic-related disorder such as hearing disorder or impairment (or balance impairment), preferably ototoxin-induced or traumatic inner ear hair cells apoptotic damage. Those in need of treatment include those already experiencing a hearing impairment, those prone to having the impairment, and those in which the impairment is to be prevented. Without being bound by theory, the hearing impairment may be due to apoptotic inner car hair cell damage or loss, wherein the damage or loss is caused by infection, mechanical injury, loud sound, aging, or, in particular, chemical-induced ototoxicity. Ototoxins include therapeutic drugs including antineoplastic agents, salicylates, quinines, and aminoglycoside antibiotics, contaminants in foods or medicinals, and environmental or industrial pollutants. Typically, treatment is performed to prevent or reduce ototoxicity, especially resulting from or expected to result from administration of therapeutic drugs. Preferably a therapeutically effective composition is given immediately after the exposure to prevent or reduce the ototoxic effect. More preferably, treatment is provided prophylactically, either by administration of the composition prior to or concomitantly with the ototoxic pharmaceutical or the exposure to the ototoxin.
By �ototoxin� in the context of the present invention is meant a substance that through its chemical action injures, impairs or inhibits the activity of the sound receptors component of the nervous system related to hearing, which in turn impairs hearing (and/or balance). In the context of the present invention, ototoxicity includes a deleterious effect on the inner ear hair cells. Ototoxic agents that cause hearing impairments include, but are not limited to, neoplastic agents such as vincristine, vinblastine, cisplatin and cisplatin-like compounds, taxol and taxol-like compounds, dideoxy-compounds, e.g., dideoxyinosine; alcohol; metals; industrial toxins involved in occupational or environmental exposure; contaminants of food or medicinals; and over-doses of vitamins or therapeutic drugs, e.g., antibiotics such as penicillin or chloramphenicol, and megadoses of vitamins A, D, or B6, salicylates, quinines and loop diuretics. By �exposure to an ototoxic agent� is meant that the ototoxic agent is made available to, or comes into contact with, a mammal. Exposure to an ototoxic agent can occur by direct administration, e.g., by ingestion or administration of a food, medicinal, or therapeutic agent, e.g., a chemotherapeutic agent, by accidental contamination, or by environmental exposure, e.g., aerial or aqueous exposure.
In another embodiment the methods of the invention are applied to hearing impairments resulting from administration of a diuretic to treat its ototoxic side-effect. Diuretics, particularly �loop� diuretics, i.e. those that act primarily in the Loop of Henle, are candidate ototoxins. Illustrative examples, not limiting to the invention method, include furosemide, ethacrylic acid, and mercurials. Diuretics are typically used to prevent or eliminate edema. Diuretics also used in nonedematous states for example hypertension, hypercalcemia, idiopathic hypercalciuria, and nephrogenic diabetes insipidus.
A �mirror� nucleotide is a nucleotide with reversed chirality to the naturally occurring or commonly employed nucleotide, i.e., a mirror image (L-nucleotide) of the naturally occurring (ID-nucleotide). The nucleotide can be a ribonucleotide or a deoxyribonucleotide and my further comprise at least one sugar, base and or backbone modification. U.S. Pat. No. 6,602,858 discloses nucleic acid catalysts comprising at least one L-nucleotide substitution.
As used herein, the term �inhibition� of p53 means inhibition of the gene expression (transcription or translation) or polypeptide activity.
By the term �antisense� (AS) or �antisense fragment� is meant a polynucleotide fragment (comprising either deoxyribonucleotides, ribonucleotides or a mixture of both) having inhibitory antisense activity, said activity causing a decrease in the expression of the endogenous genomic copy of the corresponding gene. An AS polynucleotide is a polynucleotide which comprises consecutive nucleotides having a sequence of sufficient length and homology to a sequence present within the sequence of the target gene to permit hybridization of the AS to the gene. Many reviews have covered the main aspects of antisense (AS) technology and its therapeutic potential (Aboul-Fadl T. Curr Med. Chem. 2005, 12(19):2193-214; Crooke S T, Curr Mol Med. 2004, 4(5):465-87; Crooke S T, Ann Rev Med. 2004, 55:61-95; Vacek M et al., Cell Mol Life Sci, 2003, 60(5):825-33; Cho-Chung Y S, Arch Pharm Res. 2003, 26(3):183-91. There are further reviews on the chemical (Crooke et al., Hematol Pathol. 1995, 9(2):59-72), cellular (Wagner, Nature. 1994, 372(6504):333-5) and therapeutic (Scanlon, et al, FASEB J. 1995, 9(13):1288-96) aspects of AS technology. Antisense intervention in the expression of specific genes can be achieved by the use of modified AS oligonucleotide sequences (for recent reports see Lefebvre-d'Hellencourt et al, 1995; Agrawal, 1996: LevLehman et al, 1997).
The sequence target segment for the antisense oligonucleotide is selected such that the sequence exhibits suitable energy related characteristics important for oligonucleotide duplex formation with their complementary templates, and shows a low potential for self-dimerization or self-complementation (Anazodo et al., 1996, Biochem. Biophys. Res. Comm. 229:305-309). For example, the computer program OLIGO (Primer Analysis Software, Version 3.4), can be used to determine antisense sequence melting temperature, free energy properties, and to estimate potential self-dimer formation and self-complimentary properties. The program allows the determination of a qualitative estimation of these two parameters (potential self-dimer formation and self-complimentary) and provides an indication of �no potential� or �some potential� or �essentially complete potential�. Using this program target segments are generally selected that have estimates of no potential in these parameters. However, segments can be used that have �some potential� in one of the categories. A balance of the parameters is used in the selection is known in the art. Further, the oligonucleotides are also selected as needed so that analog substitution does not substantially affect function.
A �ribozyme� is an RNA molecule that possesses RNA catalytic ability (see Cech for review) and cleaves a specific site in a target RNA. In accordance with the present invention, ribozymes which cleave mRNA may be utilized as inhibitors. This may be necessary in cases where antisense therapy is limited by stoichiometric considerations (Sarver et al., 1990, Gene Regulation and Aids, pp. 305-325). Ribozymes can then be used that will target the a gene associated with a bone marrow disease. The number of RNA molecules that are cleaved by a ribozyme is greater than the number predicted by stochiochemistry. (Hampel and Tritz, Biochem. 1989, 28(12):4929-33; Uhlenbeck, Nature. 1987 328(6131):596-600).
EXAMPLES General Methods in Molecular Biology Standard molecular biology techniques known in the art and not specifically described were generally followed as in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, New York (1989), and as in Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Baltimore, Md. (1989) and as in Perbal, A Practical Guide to Molecular Cloning, John Wiley & Sons, New York (1988), and as in Watson et al., Recombinant DNA, Scientific American Books, New York and in Birren et al (eds) Genome Analysis: A Laboratory Manual Series, Vols. 1-4 Cold Spring Harbor Laboratory Press, New York (1998) and methodology as set forth in U.S. Pat. Nos. 4,666,828; 4,683,202; 4,801,531; 5,192,659 and 5,272,057 and incorporated herein by reference. Polymerase chain reaction (PCR) was carried out generally as in PCR Protocols: A Guide To Methods And Applications, Academic Press, San Diego, Calif. (1990). In situ (In cell) PCR in combination with Flow Cytometry can be used for detection of cells containing specific DNA and mRNA sequences (Testoni et al., 1996. Blood 87:3822.) Methods of performing RT-PCR are also well known in the art.
1. Before transfection cell medium was replaced by 1500 ul fresh medium without antibiotics. 2. In sterile, plastic tube, Lipofectamine2000 reagent (5 ul per well) was added to 250 ul serum-free medium, and incubated for 5 min at room temperature. 3. In another tube 4 ug DNA (p53 gene:GFP gene, 10:1) and human p53 oligonucleotides were added to 250 ul serum free medium. 4. Lipofectamine2000 complex was combined with p53 oligonucleotides solution and incubated for 20 min at room temperature. 5. The mixture solution was added dropwise to the cells, and cells were incubated at 37� C. 6. 48 h alter transfection, cells were harvested and proteins were extracted using RIPA buffer. 7. p53 expression was determined by Western Blot analysis using monoclonal antibody (Clone240, Chemicon). For normalization, blots were examined for GFP expression.
Example 5 The Effect of p53 siRNA Treatment on Acoustic-Induced Hair Cell Death in the Cochlea of Chinchilla The activity of p53 siRNA (QM5) in an acoustic trauma model was studied in chinchilla. A group of 7 animals underwent the acoustic trauma. The animals were exposed to an octave band of noise centered at 4 kHz for 2.5 h at 105 dB. The left ear of the noise-exposed chinchillas was pre-treated (48 h before the acoustic trauma) with 30 μg of siRNA in �10 μL of saline; the right ear was pre-treated with vehicle (saline). The compound action potential (CAP) is a convenient and reliable electrophysiological method for measuring the neural activity transmitted from the cochlea. The CAP is recorded by placing an electrode near the base of the cochlea in order to detect the local field potential that is generated when a sound stimulus, such as click or tone burst, is abruptly turned on. The functional status of each ear was assessed 2.5 weeks after the acoustic trauma. Specifically, the mean threshold of the compound action potential recorded from the round window was determined 2.5 weeks after the acoustic trauma in order to determine if the thresholds in the siRNA-treated ear were lower (better) than the untreated (saline) ear. In addition, the amount of inner and outer hair cell loss was determined in the siRNA-treated and the control ear. FIG. 5 shows the mean threshold results recorded from the round window of siRNA-treated (filled circle) and saline-treated (open circle) chinchillas 2.5 weeks after the acoustic trauma. As demonstrated in FIG. 5, the mean thresholds were lower in the siRNA-treated ears versus the untreated ears. The difference at 4 kHz was statistically significant (p<0.033). These results indicate that p53 siRNA administered to the round window of the cochlea is capable of reducing the ID damage caused by acoustic trauma.
Example 6 The Effect of p53 or 801 siRNA Treatment on Cisplatin-Induced Hair Cell Death in the Cochlea of Rats Male Wistar Rats were tested for basal auditory brainstem response (ABR) thresholds for signals of clicks, 8, 16 and 32 kHz prior to cisplatin treatment. Following the basal auditory brainstem response testing, cisplatin was administered as an intraperitoneal infusion of 13 mg/kg over 30 minutes. Treated ears received either 15 ug/4 microliters of p53 siRNA (QM5 molecule in Table A) in PBS or 801 siRNA in PBS (applied directly to the round window membrane). The 801 siRNA is designated REDD14 and has the following nucleotide sequence in the sense strand: 5′-GUGCCAACCUGAUGCAGCU-3′ (SEQ ID NO: 317) and in the antisense stran: 5′-AGCUGCAUCAGGUUGGCAC-3′ (SEQ ID NO: 318). Control ears were treated with either non-related GFP siRNA or PBS. The siRNA molecules were administered between 3-5 days prior to cisplatin administration in order to permit protective effect on the cochlea.
Example 7 Model Systems of Acute Renal Failure (ARF) Testing the active siRNA for treating ARF may be done for example by using sepsis-induced ARF or ischemia-reperfusion-induced ARF
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"Pifithrin-α Supresses p53 and Protects Cochlear and Vestibular Hair Cells From Cisplatin-Induced Apoptosis," Neuroscience, 120:191-205.Referenced byCiting PatentFiling datePublication dateApplicantTitleUS8148342Jan 11, 2008Apr 3, 2012Quark Pharmaceuticals Inc.Oligoribonucleotides and methods of use thereof for treatment of alopecia, acute renal failure and other diseasesUS8168607Jun 7, 2010May 1, 2012Quark Pharmaceuticals Inc.Methods of treating eye diseases in diabetic patientsUS8404654Jul 1, 2009Mar 26, 2013Quark Pharmaceuticals, Inc.Treatment or prevention of oto-pathologies by inhibition of pro-apoptotic genesUS8431692Jun 7, 2009Apr 30, 2013Quark Pharmaceuticals, Inc.Compositions and methods for treatment of ear disordersUS8642571Aug 31, 2012Feb 4, 2014Quark Pharmaceuticals, Inc.Therapeutic uses of inhibitors of RTP801US8765699Sep 27, 2005Jul 1, 2014Quark Pharmaceuticals, Inc.Oligoribonucleotides and methods of use thereof for treatment of alopecia, acute renal failure and other diseasesWO2014043292A1Sep 12, 2013Mar 20, 2014Quark Pharmaceuticals, Inc.Double-stranded oligonucleotide molecules to p53 and methods of use thereofClassifications U.S. Classification514/44.00R, 536/24.5, 536/23.1International ClassificationA61K48/00, C07H21/02, C07H21/04Cooperative ClassificationA61K31/70European ClassificationA61K31/70Legal EventsDateCodeEventDescriptionDec 29, 2008ASAssignmentOwner name: QUARK PHARMACEUTICALS, INC., CALIFORNIAFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:FEINSTEIN, ELENA;REEL/FRAME:022055/0039Effective date: 20080116RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services©2012 Google