Compositions and methods for generating hair cells by upregulating jag-1

Abstract

Provided are compositions and methods comprising Jag-1 agonists for increasing proliferation of cochlear supporting cells or vestibular supporting cells, and related methods of treating hearing or balance disorders.

1 . A method for increasing proliferation of a cochlear supporting cell or a vestibular supporting cell, comprising contacting the supporting cell with a Jagged-1 (Jag-1) agonist, wherein the Jag-1 agonist is not a WNT agonist or a GSK3 inhibitor thereby increasing cochlear supporting cell or vestibular supporting cell proliferation compared to a vehicle control. 
     
     
         2 .- 23 . (canceled) 
     
     
         24 . A method of treating a subject who has, or is at risk of, developing an inner ear hearing or balance disorder, comprising administering to the subject:
 a. a Jagged-1 (Jag-1) agonist, wherein the Jag-1 agonist is not a Wnt agonist or a GSK3 inhibitor;   b. a Deltex-1 agonist, wherein the Deltex-1 agonist is not a Wnt agonist or a GSK3 inhibitor; or   c. a non-canonical Notch signaling agonist.   
     
     
         25 . The method of  claim 24 , wherein the subject has an inner ear hearing or balance disorder. 
     
     
         26 .- 32 . (canceled) 
     
     
         33 . The method of  claim 24 , wherein the Jag-1 agonist and/or Deltex-1 agonist is a soluble Jag-1 protein, a phosphatidylinositide 3-kinase (PI3K) agonist or a HIF1-α activator. 
     
     
         34 . The method of  claim 33 , wherein the PI3K agonist is a Forkhead box-O transcription factor (FOXO) inhibitor. 
     
     
         35 . (canceled) 
     
     
         36 . The method of  claim 33 , wherein a HIF1-α activator is 4,4α-dihydro-4-oxo-1,10-phenanthroline-3-carboxylic acid (1,4-DPCA), N-[(1-chloro-4-hydroxy-3-isoquinolinyl)carbonyl]-glycine (FG-2216) or N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxo-5-pyrimidinyl)carbonyl]-glycine (daprodusat). 
     
     
         37 .- 88 . (canceled) 
     
     
         89 . A pharmaceutical composition comprising a Jag-1 agonist and/or Deltex-1 agonist and a pharmaceutically acceptable carrier. 
     
     
         90 . The pharmaceutical composition of  claim 89 , wherein the Jag-1 agonist and/or Deltex-1 agonist is a soluble Jag-1 protein, a phosphatidylinositide 3-kinase (PI3K) agonist or a HIF1-α activator. 
     
     
         91 . The pharmaceutical composition of  claim 90 , wherein the PI3K agonist is a Forkhead box-O transcription factor (FOXO) inhibitor. 
     
     
         92 . The pharmaceutical composition of  claim 91 , wherein the FOXO inhibiter is AS1842856. 
     
     
         93 . The pharmaceutical composition of  claim 90 , wherein the HIF1-α activator is 4,4α-dihydro-4-oxo-1,10-phenanthroline-3-carboxylic acid (1,4, DPCA), N-[(1-chloro-4-hydroxy-3-isoquinolinyl)carbonyl]-glycine (FG-2216) or N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxo-5-pyrimidinyl)carbonyl]-glycine (daprodusat). 
     
     
         94 .- 125 . (canceled)