Methods and compositions for regenerating hair cells and/or supporting cells

Abstract

Provided are methods and compositions for inducing cells of the inner ear (for example, cochlear and utricular hair cells) to reenter to cell cycle and to proliferate. More particularly, the invention relates to the use of agents that increase c-myc activity and/or Notch activity for inducing cell cycle reentry and proliferation of cochlear or utricular hair cells and/or cochlear or utricular supporting cells. The methods and compositions can be used to promote the proliferation of hair cells and/or supporting cells to treat a subject at risk of or affected with, hearing loss or a subject at risk of or affected with vestibular dysfunction.

We claim: 
     
         1 . A method of inducing proliferation or cell cycle reentry of a differentiated cochlear cell or a utricular cell, the method comprising increasing both c-myc activity and Notch activity within the cell sufficient to induce proliferation or cell cycle reentry of the cochlear cell or utricular cell. 
     
     
         2 . The method of  claim 1 , wherein the cell dedifferentiates upon reentry into the cell cycle. 
     
     
         3 . The method of  claim 1 , wherein the cochlear cell or the utricular cell is a hair cell or a supporting cell. 
     
     
         4 . The method of  claim 1 , wherein c-myc activity is increased by administering an effective amount of a c-myc protein or a c-myc activator. 
     
     
         5 . The method of claim lany one of  claim 1 , wherein Notch activity is increased by administering an effective amount of a Notch protein, a Notch Intracellular Domain (NICD) protein or a Notch activator. 
     
     
         6 . The method of  claim 1 , wherein, after c-myc activity is increased, c-myc activity is inhibited to limit proliferation of the cochlear cell or utricular cell and/or to promote survival of the cochlear cell or utricular cell. 
     
     
         7 . The method of  claim 3 , wherein when the cochlear cell or the utricular cell is a supporting cell, the method further comprises the step of inhibiting Notch activity after proliferation of the supporting cell thereby to induce differentiation of the supporting cell and/or at least one of its daughter cells into a hair cell. 
     
     
         8 . The method of  claim 7 , wherein the Notch activity is inhibited by administering an effective amount of a Notch inhibitor. 
     
     
         9 . The method of  claim 3 , wherein when the cochlear cell or the utricular cell is a supporting cell, the method further comprises the step of increasing Atoh1 activity after proliferation of the supporting cell thereby to induce differentiation of the supporting cell and/or at least one of its daughter cells into a hair cell. 
     
     
         10 . A method for regenerating a cochlear or utricular hair cell, the method comprising:
 (a) increasing both c-myc activity and Notch activity within the hair cell thereby to induce cell proliferation to produce a daughter cell; and   (b) after cell proliferation, decreasing Notch activity thereby to induce differentiation of at least one of the cell and the daughter cell to produce a differentiated cochlear or utricular hair cell.   
     
     
         11 . The method of  claim 10 , wherein the cochlear cell or the utricular cell is a hair cell or a supporting cell. 
     
     
         12 . The method of  claim 10 , wherein, in step (a), c-myc is increased by contacting the cell with an effective amount of a c-myc protein or a c-myc activator. 
     
     
         13 . The method of  claim 10 , wherein, in step (b), Notch is increased by contacting the cell with an effective amount of a Notch protein, a Notch Intracellular Domain (NICD) protein or a Notch activator. 
     
     
         14 . The method of  claim 10 , wherein, in step (b), Notch activity is decreased by contacting the cell with an effective amount of a Notch inhibitor. 
     
     
         15 . The method of  claim 12 , wherein the c-myc protein or the c-myc activator is administered to an inner ear of a subject. 
     
     
         16 . The method of  claim 13 , wherein the Notch protein, NICD protein, or the Notch activator is administered to an inner ear of a subject. 
     
     
         17 . The method of  claim 14 , wherein the Notch inhibitor is administered to an inner ear of a subject.