Treatment or prevention of oto-pathologies by inhibition of pro-apoptotic genes

Abstract

The invention relates to one or more inhibitors, in particular siRNAs, which down-regulate the expression of human pro-apoptotic genes. The invention also relates to a pharmaceutical composition comprising the compound, or a vector capable of expressing the compound, and a pharmaceutically acceptable carrier. The present invention also contemplates a method of 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, comprising administering to the patient the pharmaceutical composition in a therapeutically effective dose so as to thereby treat the patient.

1 - 39 . (canceled) 
     
     
         40 . A method for reducing the incidence or severity of hearing impairment in a subject comprising administering to the subject a composition comprising an amount of a p53 polynucleotide inhibitor effective to treat the subject, wherein the polynucleotide inhibitor is an unmodified or chemically modified siRNA, a vector comprising an siRNA, a vector which expresses an siRNA or a molecule which is endogenously processed into an siRNA. 
     
     
         41 . The method of  claim 40 , wherein the polynucleotide inhibitor is a chemically modified siRNA. 
     
     
         42 . The method of  claim 40 , wherein the hearing impairment is selected from the group consisting of acoustic trauma-induced hearing loss, mechanical trauma-induced hearing loss, and ototoxin-induced hearing loss induced by an ototoxin. 
     
     
         43 . The method of  claim 42 , wherein the ototoxin is a chemotherapeutic agent selected from the group consisting of cisplatin or a cisplatin-like compound, an aminoglycoside antibiotic, a salicylate or salicylate-like compound, a quinine or quinine-like compound, and a loop-diuretic drug. 
     
     
         44 . The method of  claim 40 , wherein the polynucleotide inhibitor is applied to the round window membrane of the cochlea. 
     
     
         45 . The method of  claim 40 , wherein the polynucleotide inhibitor is applied as liquid drops to the ear canal. 
     
     
         46 . A pharmaceutical composition comprising an amount of a p53 polynucleotide inhibitor effective to reduce the incidence or severity of hearing impairment in a subject, and a pharmaceutically acceptable carrier, wherein the polynucleotide inhibitor is an unmodified or chemically modified siRNA, a vector comprising an siRNA, a vector which expresses an siRNA and a molecule which is endogenously processed into an siRNA. 
     
     
         47 . The composition of  claim 46 , wherein the polynucleotide inhibitor is a chemically modified siRNA. 
     
     
         48 . The composition of  claim 46 , wherein the composition is in a form of liquid ear drops. 
     
     
         49 . The composition of  claim 46 , wherein the composition is in a form of an injectable solution. 
     
     
         50 . The composition of  claim 47 , wherein the siRNA comprises at least one ribonucleotide modified in its sugar residue. 
     
     
         51 . The composition of  claim 50 , wherein the modified sugar residue in at least one ribonucleotide comprises a 2′-O-methyl modification.