Combination therapies for inner ear sensory hair cell regeneration/replacement

Abstract

The present disclosure relates to compositions and methods for the regeneration and/or restoration of hair cells utilizing a composition or an agent that decreases expression of a gene in a tissue of the inner ear and a second agent.

1 - 33 . (canceled) 
     
     
         34 . A method of treating hearing loss or balance dysfunction in a subject comprising:
 applying to the inner ear of a subject in need thereof a therapeutically effective amount of a GSK-3 inhibitor, and   applying to the inner ear of said subject an amount of a composition sufficient to decrease the expression of a Hes1 gene in a tissue of the inner ear.   
     
     
         35 . The method of  claim 34 , wherein the GSK-3 inhibitor is selected from 6-bromoindirubin-3′-oxime (BIO), tideglusib (TIDE), lithium chloride, and SB-216763. 
     
     
         36 . The method of  claim 34 , wherein the composition sufficient to decrease the expression of a Hes1 gene in a tissue of the inner ear comprises a nanoparticle, or a lipofection formulation, and wherein the nanoparticle or lipofection formulation comprises an agent that decreases expression of a Hes1 gene in a tissue of the inner ear. 
     
     
         37 . The method of  claim 34 , wherein the composition sufficient to decrease the expression of a Hes1 gene in a tissue of the inner ear comprises an siRNA, shRNA, miRNA, antisense oligonucleotides (ASOs), and/or a nucleic acid comprising one or more modified nucleic acid residues. 
     
     
         38 . The method of  claim 37 , wherein the siRNA molecule comprises one or more of pairs of sequences selected from the group consisting of SEQ ID NO: 1, and SEQ ID NO: 2; (b) SEQ ID NO: 3 and SEQ ID NO: 4; (c) SEQ ID NO: 5 and SEQ ID NO: 6; (d) SEQ ID NO: 7 and SEQ ID NO: 8; (e) SEQ ID NO: 9 and SEQ ID NO: 10; (f) SEQ ID NO: 11 and SEQ ID NO: 12; (g) SEQ ID NO: 13 and SEQ ID NO: 14. 
     
     
         39 . The method of  claim 36 , wherein the agent that decreases expression of a Hes1 gene in the tissue of the inner ear is an siRNA molecule. 
     
     
         40 . The method of  claim 36 , wherein the nanoparticle further comprises a biodegradable polymer. 
     
     
         41 . The method of  claim 40 , wherein the biodegradable polymer is poly(lactic-co-glycolic acid) (PLGA) or pegylated PLGA (PEG-PLGA). 
     
     
         42 . The method of  claim 36 , wherein the nanoparticle further comprises a magnetically responsive particle. 
     
     
         43 . The method of  claim 42 , wherein the magnetically responsive particle is superpararmagnetic iron oxide (SPION). 
     
     
         44 . The method of  claim 42 , further comprising using magnetic force to transport the nanoparticles across the round or oval window membrane. 
     
     
         45 . The method of  claim 34 , further comprising applying to the inner ear of a subject in need thereof a therapeutically effective amount of FGF2. 
     
     
         46 . The method of  claim 34 , wherein one or more of the applying steps comprise transtympanic administration, intracochlear injection, intracochlear infusion, or using ear drops. 
     
     
         47 . The method of  claims 34 , wherein the GSK-3 inhibitor is applied before applying the composition sufficient to decrease the expression of a Hes1 gene in a tissue of the inner ear. 
     
     
         48 . The method of  claims 34 , wherein the GSK-3 inhibitor is applied after applying the composition sufficient to decrease the expression of a Hes1 gene in a tissue of the inner ear. 
     
     
         49 . The method of  claim 34 , wherein both the GSK-3 inhibitor and the composition sufficient to decrease the expression of a Hes1 gene in a tissue of the inner ear are applied simultaneously. 
     
     
         50 . A method of replacing, regenerating, and/or protecting hair cells in the inner ear of a subject comprising:
 applying to the inner ear of a subject in need thereof a therapeutically effective amount of a GSK-3 inhibitor, wherein the GSK-3 inhibitor is capable of inducing a mitotic response in the inner ear of the subject and   applying to the inner ear of said subject an amount of a composition sufficient to decrease the expression of a Hes1 gene in a tissue of the inner ear.   
     
     
         51 . The method of  claim 50 , wherein the GSK-3 inhibitor is selected from 6-bromoindirubin-3′-oxime (BIO) and tideglusib (TIDE). 
     
     
         52 . The method of  claim 50 , wherein the composition sufficient to decrease the expression of a Hes1 gene in a tissue of the inner ear comprises a nanoparticle, or a lipofection formulation, an wherein the nanoparticle or lipofection formulation comprises an agent that decreases expression of a Hes1 gene in a tissue of the inner ear. 
     
     
         53 . The method of  claim 52 , wherein the agent that decreases expression of a Hes1 gene in a tissue of the inner ear is a siRNA molecule.