US2022339154A1PendingUtilityA1

Compositions, systems, and methods for generating inner ear hair cells for treatment of hearing loss

75
Assignee: MASSACHUSETTS INST TECHNOLOGYPriority: Sep 3, 2014Filed: Jun 27, 2022Published: Oct 27, 2022
Est. expirySep 3, 2034(~8.1 yrs left)· nominal 20-yr term from priority
Inventors:Jeffrey M. KarpRobert S. LangerXiaolei YinNitin Joshi
C12N 2501/999A61K 31/422C12N 2501/42C12N 2501/115C12N 5/062A61K 31/5377A61K 35/36A61K 9/0046A61P 27/16C12N 2501/415C12N 5/0627A61K 31/19A61K 31/5517C12N 2501/727A61K 31/506C12N 2501/105A61K 31/55A61P 43/00A61K 31/167A61K 33/00A61K 31/437C12N 2501/11A61K 31/4709C12N 2501/73A61K 2300/00C12N 2500/38C12N 2501/15
75
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Cited by
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Claims

Abstract

Method and compositions for inducing the self-renewal of stem/progenitor supporting cells comprised by a cochlear cell population, including inducing the stem/progenitor cells to proliferate while maintaining, in the daughter cells, the capacity to differentiate into hair cells.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method for treating hearing loss in a subject having hearing loss, the method comprising administering intratympanically or transtympanically to a subject a composition comprising:
 i) a biocompatible matrix having dispersed therein:   a)   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; and
 b) valproic acid, or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The method of  claim 1 , wherein:
 the CHIR99021, or pharmaceutically acceptable salt thereof, is between about 0.01 wt % and about 50 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.01 wt % and about 50 wt % of the composition.   
     
     
         3 . The method of  claim 1 , wherein:
 the CHIR99021, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 50 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 50 wt % of the composition.   
     
     
         4 . The method of  claim 1 , wherein:
 the CHIR99021, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 40 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % to about 40 wt % of the composition.   
     
     
         5 . The method of  claim 1 , wherein:
 the CHIR99021, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 30 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % to about 30 wt % of the composition.   
     
     
         6 . The method of  claim 1 , wherein:
 the CHIR99021, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 20 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 20 wt % of the composition.   
     
     
         7 . The method of  claim 1 , wherein:
 the CHIR99021, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 10 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 10 wt % of the composition.   
     
     
         8 . The method of  claim 1 , wherein:
 the CHIR99021, or pharmaceutically acceptable salt thereof, is between about 0.1 mg/mL to about 70 mg/mL of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.01% to about 50% the composition.   
     
     
         9 . The method of  claim 1 , wherein the CHIR99021, or pharmaceutically acceptable salt thereof, is in lyophilized form. 
     
     
         10 . The method of  claim 1 , wherein the valproic acid, or pharmaceutically acceptable salt thereof, is in lyophilized form. 
     
     
         11 . The method of  claim 1 , wherein the CHIR99021, or pharmaceutically acceptable salt thereof, is in hydrated form. 
     
     
         12 . The method of  claim 1 , wherein the valproic acid, or pharmaceutically acceptable salt thereof, is in hydrated form. 
     
     
         13 . The method of  claim 1 , wherein the biocompatible matrix comprises one or more of hyaluronic acid, hyaluronates, lecithin gels, pluronics, poly(ethyleneglycol), poloxamers, chitosans, xyloglucans, collagens, fibrins, polyesters, poly(lactides), poly(glycolide), poly(lactic-co-glycolic acid (PLGA), sucrose acetate isobutyrate, glycerol monooleate, poly anhydrides, poly caprolactone sucrose, or glycerol monooleate or a combination thereof. 
     
     
         14 . The method of  claim 1 , wherein the biocompatible matrix comprises a poloxamer. 
     
     
         15 . The method of  claim 14 , wherein the poloxamer is Poloxamer 407. 
     
     
         16 . The method of  claim 1 , wherein the biocompatible matrix comprises hyaluronic acid. 
     
     
         17 . The method of  claim 1 , wherein the biocompatible matrix is a hydrogel. 
     
     
         18 . The method of  claim 1 , wherein the biocompatible matrix is a biocompatible gel or foam. 
     
     
         19 . The method of  claim 1 , wherein the composition is a controlled release formulation. 
     
     
         20 . The method of  claim 19 , wherein the controlled release formulation when administered to a subject intratympanically or transtympanically imparts an immediate release, a delayed release, a sustained release, an extended release, a variable release, a pulsatile release, or a bi-modal release of one or more of a) the GSK3β inhibitor or Wnt agonist, or a pharmaceutically acceptable salt thereof; and b) the Notch agonist or HDAC inhibitor, or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The method of  claim 1 , wherein the method produces a population of Lgr5+ cells that are in s-phase. 
     
     
         22 . The method of  claim 1 , wherein administering intratympanically or transtympanically the composition to a subject results in improved auditory functioning of the subject. 
     
     
         23 . The method of  claim 1 , wherein administering is intratympanically. 
     
     
         24 . The method of  claim 1 , wherein administering is transtympanically. 
     
     
         25 . A method for treating hearing loss in a subject having hearing loss, the method comprising administering intratympanically or transtympanically to a subject a composition comprising:
 i) a biocompatible matrix having dispersed therein:
 a) LY2090314, or a pharmaceutically acceptable salt thereof; and 
 b) valproic acid, or a pharmaceutically acceptable salt thereof. 
   
     
     
         26 . The method of  claim 25 , wherein:
 the LY2090314, or pharmaceutically acceptable salt thereof, is between about 0.01 wt % and about 50 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.01 wt % and about 50 wt % of the composition.   
     
     
         27 . The method of  claim 25 , wherein:
 the LY2090314, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 50 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 50 wt % of the composition.   
     
     
         28 . The method of  claim 25 , wherein:
 the LY2090314, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 40 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % to about 40 wt % of the composition.   
     
     
         29 . The method of  claim 25 , wherein:
 the LY2090314, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 30 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % to about 30 wt % of the composition.   
     
     
         30 . The method of  claim 25 , wherein:
 the LY2090314, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 20 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 20 wt % of the composition.   
     
     
         31 . The method of  claim 25 , wherein:
 the LY2090314, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 10 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 10 wt % of the composition.   
     
     
         32 . The method of  claim 25 , wherein:
 the LY2090314, or pharmaceutically acceptable salt thereof, is between about 0.1 mg/mL to about 70 mg/mL of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.01% to about 50% the composition.   
     
     
         33 . The method of  claim 25 , wherein the LY2090314, or pharmaceutically acceptable salt thereof, is in lyophilized form. 
     
     
         34 . The method of  claim 25 , wherein the valproic acid, or pharmaceutically acceptable salt thereof, is in lyophilized form. 
     
     
         35 . The method of  claim 25 , wherein the LY2090314, or pharmaceutically acceptable salt thereof, is in hydrated form. 
     
     
         36 . The method of  claim 25 , wherein the valproic acid, or pharmaceutically acceptable salt thereof, is in hydrated form. 
     
     
         37 . The method of  claim 25 , wherein the biocompatible matrix comprises one or more of hyaluronic acid, hyaluronates, lecithin gels, pluronics, poly(ethyleneglycol), poloxamers, chitosans, xyloglucans, collagens, fibrins, polyesters, poly(lactides), poly(glycolide), poly(lactic-co-glycolic acid (PLGA), sucrose acetate isobutyrate, glycerol monooleate, poly anhydrides, poly caprolactone sucrose, or glycerol monooleate or a combination thereof. 
     
     
         38 . The method of  claim 25 , wherein the biocompatible matrix comprises a poloxamer. 
     
     
         39 . The method of  claim 38 , wherein the poloxamer is Poloxamer 407. 
     
     
         40 . The method of  claim 25 , wherein the biocompatible matrix comprises hyaluronic acid. 
     
     
         41 . The method of  claim 25 , wherein the biocompatible matrix is a hydrogel. 
     
     
         42 . The method of  claim 25 , wherein the biocompatible matrix is a biocompatible gel or foam. 
     
     
         43 . The method of  claim 25 , wherein the composition is a controlled release formulation. 
     
     
         44 . The method of  claim 43 , wherein the controlled release formulation when administered to a subject intratympanically or transtympanically imparts an immediate release, a delayed release, a sustained release, an extended release, a variable release, a pulsatile release, or a bi-modal release of one or more of a) the GSK3β inhibitor or Wnt agonist, or a pharmaceutically acceptable salt thereof; and b) the Notch agonist or HDAC inhibitor, or a pharmaceutically acceptable salt thereof. 
     
     
         45 . The method of  claim 25 , wherein the method produces a population of Lgr5+ cells that are in s-phase. 
     
     
         46 . The method of  claim 25 , wherein administering intratympanically or transtympanically the composition to a subject results in improved auditory functioning of the subject. 
     
     
         47 . The method of  claim 25 , wherein administering is intratympanically. 
     
     
         48 . The method of  claim 25 , wherein administering is transtympanically. 
     
     
         49 . A kit for treating hearing loss in a subject having hearing loss, the kit comprising:
 i) a composition comprising a biocompatible matrix having dispersed therein:   a) lyophilized   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, and
 b) lyophilized valproic acid, or a pharmaceutically acceptable salt thereof, 
 ii) water. 
 
     
     
         50 . The kit of  claim 49 , wherein:
 the CHIR99021, or pharmaceutically acceptable salt thereof, is between about 0.01 wt % and about 50 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.01 wt % and about 50 wt % of the composition.   
     
     
         51 . The kit of  claim 49 , wherein:
 the CHIR99021, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 50 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 50 wt % of the composition.   
     
     
         52 . The kit of  claim 49 , wherein:
 the CHIR99021, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 40 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % to about 40 wt % of the composition.   
     
     
         53 . The kit of  claim 49 , wherein:
 the CHIR99021, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 30 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % to about 30 wt % of the composition.   
     
     
         54 . The kit of  claim 49 , wherein:
 the CHIR99021, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 20 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 20 wt % of the composition.   
     
     
         55 . The kit of  claim 49 , wherein:
 the CHIR99021, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 10 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 10 wt % of the composition.   
     
     
         56 . The kit of  claim 49 , wherein:
 the CHIR99021, or pharmaceutically acceptable salt thereof, is between about 0.1 mg/mL to about 70 mg/mL of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.01% to about 50% the composition.   
     
     
         57 . The kit of  claim 49 , wherein the biocompatible matrix comprises one or more of hyaluronic acid, hyaluronates, lecithin gels, pluronics, poly(ethyleneglycol), poloxamers, chitosans, xyloglucans, collagens, fibrins, polyesters, poly(lactides), poly(glycolide), poly(lactic-co-glycolic acid (PLGA), sucrose acetate isobutyrate, glycerol monooleate, poly anhydrides, poly caprolactone sucrose, or glycerol monooleate or a combination thereof. 
     
     
         58 . The kit of  claim 49 , wherein the biocompatible matrix comprises a poloxamer. 
     
     
         59 . The kit of  claim 58 , wherein the poloxamer is Poloxamer 407. 
     
     
         60 . The kit of  claim 49 , wherein the biocompatible matrix comprises hyaluronic acid. 
     
     
         61 . The kit of  claim 49 , wherein after combining the composition with the water, the biocompatible matrix is a hydrogel. 
     
     
         62 . The kit of  claim 49 , wherein after combining the composition with the water, the biocompatible matrix is a biocompatible gel or foam. 
     
     
         63 . The kit of  claim 49 , wherein after combining the composition with the water, the composition is a controlled release formulation. 
     
     
         64 . The kit of  claim 63 , wherein the controlled release formulation when administered to a subject intratympanically or transtympanically imparts an immediate release, a delayed release, a sustained release, an extended release, a variable release, a pulsatile release, or a bi-modal release of one or more of a) the GSK3β inhibitor or Wnt agonist, or a pharmaceutically acceptable salt thereof; and b) the Notch agonist or HDAC inhibitor, or a pharmaceutically acceptable salt thereof. 
     
     
         65 . A kit for treating hearing loss in a subject having hearing loss, the kit comprising:
 i) a composition comprising a biocompatible matrix having dispersed therein:
 a) lyophilized LY2090314, or a pharmaceutically acceptable salt thereof, and 
 b) lyophilized valproic acid, or a pharmaceutically acceptable salt thereof, 
   ii) water.   
     
     
         66 . The kit of  claim 65 , wherein:
 the LY2090314, or pharmaceutically acceptable salt thereof, is between about 0.01 wt % and about 50 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.01 wt % and about 50 wt % of the composition.   
     
     
         67 . The kit of  claim 65 , wherein:
 the LY2090314, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 50 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 50 wt % of the composition.   
     
     
         68 . The kit of  claim 65 , wherein:
 the LY2090314, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 40 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % to about 40 wt % of the composition.   
     
     
         69 . The kit of  claim 65 , wherein:
 the LY2090314, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 30 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % to about 30 wt % of the composition.   
     
     
         70 . The kit of  claim 65 , wherein:
 the LY2090314, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 20 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 20 wt % of the composition.   
     
     
         71 . The kit of  claim 65 , wherein:
 the LY2090314, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 10 wt % of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 10 wt % of the composition.   
     
     
         72 . The kit of  claim 65 , wherein:
 the LY2090314, or pharmaceutically acceptable salt thereof, is between about 0.1 mg/mL to about 70 mg/mL of the composition; and   the valproic acid, or pharmaceutically acceptable salt thereof, is between about 0.01% to about 50% the composition.   
     
     
         73 . The kit of  claim 65 , wherein the biocompatible matrix comprises one or more of hyaluronic acid, hyaluronates, lecithin gels, pluronics, poly(ethyleneglycol), poloxamers, chitosans, xyloglucans, collagens, fibrins, polyesters, poly(lactides), poly(glycolide), poly(lactic-co-glycolic acid (PLGA), sucrose acetate isobutyrate, glycerol monooleate, poly anhydrides, poly caprolactone sucrose, or glycerol monooleate or a combination thereof. 
     
     
         74 . The kit of  claim 65 , wherein the biocompatible matrix comprises a poloxamer. 
     
     
         75 . The kit of  claim 74 , wherein the poloxamer is Poloxamer 407. 
     
     
         76 . The kit of  claim 65 , wherein the biocompatible matrix comprises hyaluronic acid. 
     
     
         77 . The kit of  claim 65 , wherein after combining the composition with the water, the biocompatible matrix is a hydrogel. 
     
     
         78 . The kit of  claim 65 , wherein after combining the composition with the water, the biocompatible matrix is a biocompatible gel or foam. 
     
     
         79 . The kit of  claim 65 , wherein after combining the composition with the water, the composition is a controlled release formulation. 
     
     
         80 . The kit of  claim 79 , wherein the controlled release formulation when administered to a subject intratympanically or transtympanically imparts an immediate release, a delayed release, a sustained release, an extended release, a variable release, a pulsatile release, or a bi-modal release of one or more of a) the GSK3β inhibitor or Wnt agonist, or a pharmaceutically acceptable salt thereof; and b) the Notch agonist or HDAC inhibitor, or a pharmaceutically acceptable salt thereof.

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