Pathways to Generate Hair Cells

Abstract

This disclosure relates to methods and compositions for modulating (e.g., increasing) Atoh1 activity (e.g., biological activity) and/or expression (e.g., transcription and/or translation) in vivo and/or in vitro, e.g., in a biological cell and/or in a subject. The methods and compositions described herein can be used in the treatment of diseases and/or disorders that would benefit from increased Atoh1 expression in a biological cell.

1 - 43 . (canceled) 
     
     
         44 . A method of treating a subject who has an auditory disorder as a result of loss of auditory hair cells, the method comprising administering to the middle or inner ear of the subject a composition comprising a beta-catenin polypeptide and/or DNA encoding a beta-catenin polypeptide, in an amount effective to increase the number of auditory hair cells in the subject, thereby treating the auditory disorder as a result of loss of auditory hair cells in the subject. 
     
     
         45 . The method of  claim 44 , wherein the subject has one or more of sensorineural hearing loss, auditory neuropathy, or vestibular dysfunction, as a result of loss of auditory hair cells. 
     
     
         46 . The method of  claim 44 , wherein the composition further comprises a glycogen synthase kinase 3 β (GSK3β) inhibitor. 
     
     
         47 . The method of  claim 46 , wherein the GSK3β inhibitor is lithium chloride, purvalanol A, olomoucine, alsterpaullone, kenpaullone, benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione, 2-thio(3-iodobenzyl)-5-(1-pyridyl)[1,3,4]-oxadiazole, 2,4-dibenzyl-5-oxothiadiazolidine-3-thione, (2′Z,3′E)-6-bromoindirubin-3′-oxime (BIO), a 4 dibromoacetophenone, 2-chloro-1-(4,5-dibromo-thiophen-2-yl)-ethanone, N-(4-nethoxybenzyl)-N′-(5-nitro-1,3-thiazol-2-yl)urea, 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione, 2-thio(3-iodobenzyl)-5-(1-pyridyl)-[1,3,4]-oxadiazole, 2,4-dibenzyl-5-oxothiadiazolidine-3-thione, .alpha.-4-dibromoacetophenone, 2-chloro-1-(4, 5-dibromo-thiophen-2-yl)-ethanone, or N-(4-Methoxybenzyl)-N′-(5-nitro-1,3-thiazol-2-yl)urea. 
     
     
         48 . The method of  claim 46 , wherein the GSK3β inhibitor is an indirubin. 
     
     
         49 . The method of  claim 48 , wherein the indirubin is indirubin-5-sulfonamide, indirubin-5-sulfonic acid (2-hydroxyethyl)-amide, indirubin-3′-monoxime; 5-iodo-indirubin-3′-monoxime, 5-fluoroindirubin, 5, 5′-dibromoindirubin, 5-nitroindirubin, 5-chloroindirubin, 5-methylindirubin, or 5-bromoindirubin. 
     
     
         50 . The method of  claim 47 , wherein the GSK3β inhibitor is (2′Z,3′E)-6-bromoindirubin-3′-oxime (BIO). 
     
     
         51 . The method of  claim 44 , wherein the composition is injected into the luminae of the cochlea. 
     
     
         52 . The method of  claim 44 , wherein the method comprises administering the composition to the middle ear of the subject. 
     
     
         53 . The method of  claim 44 , wherein the method comprises administering the composition to the inner ear of the subject. 
     
     
         54 . The method of  claim 44 , wherein the auditory hair cell expresses atonal protein homologue 1 (Atoh1). 
     
     
         55 . The method of  claim 44 , wherein the composition further comprises an inhibitor of the Notch signaling pathway. 
     
     
         56 . The method of  claim 55 , wherein the inhibitor of the Notch signaling pathway is a γ-secretase inhibitor. 
     
     
         57 . A method of treating a subject who has an auditory disorder as a result of loss of auditory hair cells, the method comprising administering to the middle or inner ear of the subject an active agent consisting of a casein kinase 1 (CK1) inhibitor in an amount effective to increase the number of auditory hair cells in the subject, thereby treating the auditory disorder as a result of loss of auditory hair cells in the subject. 
     
     
         58 . The method of  claim 57 , wherein the subject has one or more of sensorineural hearing loss, auditory neuropathy, or vestibular dysfunction, as a result of loss of auditory hair cells. 
     
     
         59 . The method of  claim 57 , wherein the composition is injected into the luminae of the cochlea. 
     
     
         60 . The method of  claim 57 , wherein the method comprises administering the composition to the middle ear of the subject. 
     
     
         61 . The method of  claim 57 , wherein the method comprises administering the composition to the inner ear of the subject. 
     
     
         62 . The method of  claim 57 , wherein the auditory hair cell expresses atonal protein homologue 1 (Atoh1).