Treating Hearing Loss

Abstract

This invention relates to methods for treating hearing loss associated with loss of cochlear hair cells, e.g., caused by noise exposure, using certain gamma secretase inhibitors, in post-neonatal animals, e.g., adolescents and adults.

What is claimed is: 
     
         1 . A method of treating hearing loss caused by loss of cochlear hair cells in a post-neonatal mammal, the method comprising locally administering to the ear of the mammal a composition comprising a therapeutically effective amount of a Notch inhibitor, e.g., a gamma secretase inhibitor, wherein the therapeutically effective amount is an amount sufficient to restore hearing at one or more frequencies. 
     
     
         2 . The method of  claim 1 , wherein the hearing loss was caused by exposure to a physical or chemical ototoxic insult. 
     
     
         3 . The method of  claim 2 , wherein the physical ototoxic insult is noise. 
     
     
         4 . The method of  claim 2 , wherein the composition is administered to the ear within four weeks, two weeks, one week, or one day of the exposure to the insult. 
     
     
         5 . The method of  claim 1 , wherein the composition is applied topically to the round window. 
     
     
         6 . The method of  claim 1 , wherein the composition further comprises a sustained release carrier. 
     
     
         7 . The method of  claim 6 , wherein the carrier is a polyoxyethylene-polyoxypropylene triblock copolymer. 
     
     
         8 . The method of  claim 1 , wherein the composition comprises at least 10 mM of the Notch inhibitor. 
     
     
         9 . The method of  claim 1 , further comprising determining a baseline level of hearing at one or more frequencies before administering the composition, and a subsequent level of hearing at the same one or more frequencies after administering the composition, and administering one or more additional doses of the composition until a desired level of hearing at the one or more frequencies is recovered. 
     
     
         10 . The method of  claim 9 , wherein the subsequent level of hearing is determined one week, two weeks, three weeks, one month, two months, three months, four months, six months, and/or twelve months after administering the composition. 
     
     
         11 . The method of any of the preceding claims, wherein the gamma secretase inhibitor is selected from the group consisting of RO4929097; DAPT (N-[(3,5-Difluorophenyl)acetyl]-L-alanyl-2-phenyl]glycine-1,1-dimethylethyl ester); L-685458 ((5S)-(t-Butoxycarbonylamino)-6-phenyl-(4R)hydroxy-(2R)benzylhexanoyl)-L-leu-L-phe-amide); BMS-708163 (Avagacestat); BMS-299897 (2-[(1R)-1-[[(4-Chlorophenyl)sulfonyl](2,5-difluorophenyl)amino]ethyl-5-fluorobenzenebutanoic acid); MK-0752; YO-01027; MDL28170 (Sigma); LY411575 (N-2((25)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-1-alaninamide); ELN-46719 (2-hydroxy-valeric acid amide analog of LY411575; PF-03084014 ((S)-2-((S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide); Compound E ((2S)-2-{[(3,5-Diflurophenyl)acetyl]amino}-N-[(3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide; and Semagacestat (LY450139; (2S)-2-hydroxy-3-methyl-N-((1S)-1-methyl-2-{[(1S)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl]amino}-2-oxoethyl)butanamide), or pharmaceutically acceptable salts thereof. 
     
     
         12 . The method of any of the preceding claims, wherein the gamma secretase inhibitor is LY411575 (N-2((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-1-alaninamide). 
     
     
         13 . The method of any of the preceding claims, wherein the mammal is a child, adolescent or adult, e.g., above the age of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 years. 
     
     
         14 . The method of any of the preceding claims, wherein the mammal is an adult of at least 40 years of age, e.g., at least 45, 50, 55, 60, 65, 70 years of age. 
     
     
         15 . The method of any of the preceding claims, wherein the mammal is a human.