Compositions, systems, and methods for generating inner ear hair cells for treatment of hearing loss
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.
1. A composition comprising:
i) a biocompatible matrix having dispersed therein:
a) a GSK3β inhibitor or Wnt agonist, or a pharmaceutically acceptable salt thereof; and
b) a Notch agonist or HDAC inhibitor, or a pharmaceutically acceptable salt thereof;
wherein the biocompatible matrix comprises a poloxamer.
2. The composition of claim 1 , wherein the composition is a controlled release formulation.
3. The composition of claim 2 , wherein the controlled release formulation when administered to a subject trans-tympanically 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.
4. The composition of claim 1 , wherein the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is selected from CHIR99021, LY2090314, lithium, A1070722, BML-284 and SKL2001, or a pharmaceutically acceptable salt thereof.
5. The composition of claim 1 , wherein the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is:
or a pharmaceutically acceptable salt thereof.
6. The composition of claim 1 , wherein the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is selected from valproic acid, SAHA and Tubastatin A, or a pharmaceutically acceptable salt thereof.
7. The composition of claim 1 , wherein the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is:
or a pharmaceutically acceptable salt thereof.
8. The composition of claim 1 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is selected from CHIR99021, LY2090314, lithium, A1070722, BML-284 and SKL2001, or a pharmaceutically acceptable salt thereof; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is selected from valproic acid, SAHA and Tubastatin A, or a pharmaceutically acceptable salt thereof.
9. The composition of claim 1 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is CHIR99021, or a pharmaceutically acceptable salt thereof; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is valproic acid, or a pharmaceutically acceptable salt thereof.
10. The composition of claim 1 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.01 wt % and about 50 wt % of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.01 wt % and about 50 wt % of the composition.
11. The composition of claim 1 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 50 wt % of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 50 wt % of the composition.
12. The composition of claim 1 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 40 wt % of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % to about 40 wt % of the composition.
13. The composition of claim 1 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 30 wt % of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % to about 30 wt % of the composition.
14. The composition of claim 1 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 20 wt % of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 20 wt % of the composition.
15. The composition of claim 1 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 10 wt % of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 10 wt % of the composition.
16. The composition of claim 1 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.1 mg/mL to about 70 mg/mL of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.01% to about 50% the composition.
17. The composition of claim 1 , wherein the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, and the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, are in lyophilized form.
18. The composition of claim 1 , wherein the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, and the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, are in hydrated form.
19. The composition of claim 1 , wherein the poloxamer is Poloxamer 407.
20. A composition comprising:
i) a biocompatible matrix having dispersed therein:
a) a GSK3β inhibitor or Wnt agonist, or a pharmaceutically acceptable salt thereof, wherein the GSK3β inhibitor or Wnt agonist is selected from CHIR99021, LY2090314, lithium, A1070722, BML-284 and SKL2001, or a pharmaceutically acceptable salt thereof; and
b) a Notch agonist or HDAC inhibitor, or a pharmaceutically acceptable salt thereof;
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.
21. The composition of claim 20 , wherein the biocompatible matrix is a biocompatible gel or foam.
22. The composition of claim 20 , wherein the composition is a controlled release formulation.
23. The composition of claim 22 , wherein the controlled release formulation when administered to a subject trans-tympanically 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.
24. The composition of claim 20 , wherein the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is:
or a pharmaceutically acceptable salt thereof.
25. The composition of claim 20 , wherein the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is selected from valproic acid, SAHA and Tubastatin A, or a pharmaceutically acceptable salt thereof.
26. The composition of claim 20 , wherein the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is:
or a pharmaceutically acceptable salt thereof.
27. The composition of claim 20 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.01 wt % and about 50 wt % of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.01 wt % and about 50 wt % of the composition.
28. The composition of claim 20 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 50 wt % of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 50 wt % of the composition.
29. The composition of claim 20 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 40 wt % of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % to about 40 wt % of the composition.
30. The composition of claim 20 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 30 wt % of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % to about 30 wt % of the composition.
31. The composition of claim 20 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 20 wt % of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 20 wt % of the composition.
32. The composition of claim 20 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 10 wt % of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 10 wt % of the composition.
33. The composition of claim 20 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.1 mg/mL to about 70 mg/mL of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.01% to about 50% the composition.
34. The composition of claim 20 , wherein the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, and the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, are in lyophilized form.
35. The composition of claim 20 , wherein the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, and the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, are in hydrated form.
36. The composition of claim 20 , wherein the biocompatible matrix is a hydrogel.
37. The composition of claim 36 , wherein the biocompatible matrix comprises hyaluronic acid.
38. The composition of claim 20 , wherein the GSK3β inhibitor or Wnt agonist is LY2090314, or pharmaceutically acceptable salt thereof.
39. The composition of claim 20 , wherein the GSK3β inhibitor or Wnt agonist is lithium, or pharmaceutically acceptable salt thereof.
40. The composition of claim 20 , wherein the GSK3β inhibitor or Wnt agonist is A1070722, or pharmaceutically acceptable salt thereof.
41. The composition of claim 20 , wherein the GSK3β inhibitor or Wnt agonist is BML-284, or pharmaceutically acceptable salt thereof.
42. The composition of claim 20 , wherein the GSK3β inhibitor or Wnt agonist is SKL2001, or pharmaceutically acceptable salt thereof.
43. The composition of claim 9 , wherein the poloxamer is Poloxamer 407.
44. The composition of claim 9 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 10 wt % of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 20 wt % of the composition.
45. The composition of claim 43 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 10 wt % of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 20 wt % of the composition.
46. A composition comprising:
i) a biocompatible matrix having dispersed therein:
a) a GSK3β inhibitor or Wnt agonist, or a pharmaceutically acceptable salt thereof; and
b) a Notch agonist or HDAC inhibitor, or a pharmaceutically acceptable salt thereof, wherein the Notch agonist or HDAC inhibitor is selected from valproic acid, SAHA and Tubastatin A;
wherein the biocompatible matrix comprises one or more of hyaluronic acid, hyaluronates, lecithin gels, pluronics, poly(ethyleneglycol), 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.
47. The composition of claim 46 , wherein the biocompatible matrix is a biocompatible gel or foam.
48. The composition of claim 46 , wherein the composition is a controlled release formulation.
49. The composition of claim 48 , wherein the controlled release formulation when administered to a subject trans-tympanically 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.
50. The composition of claim 46 , wherein the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is:
or a pharmaceutically acceptable salt thereof.
51. The composition of claim 46 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.01 wt % and about 50 wt % of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.01 wt % and about 50 wt % of the composition.
52. The composition of claim 46 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 50 wt % of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 50 wt % of the composition.
53. The composition of claim 46 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 40 wt % of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % to about 40 wt % of the composition.
54. The composition of claim 46 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 30 wt % of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % to about 30 wt % of the composition.
55. The composition of claim 46 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 20 wt % of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 20 wt % of the composition.
56. The composition of claim 46 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 10 wt % of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.1 wt % and about 10 wt % of the composition.
57. The composition of claim 46 , wherein:
the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, is between about 0.1 mg/mL to about 70 mg/mL of the composition; and
the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, is between about 0.01% to about 50% the composition.
58. The composition of claim 46 , wherein the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, and the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, are in lyophilized form.
59. The composition of claim 46 , wherein the GSK3β inhibitor or Wnt agonist, or pharmaceutically acceptable salt thereof, and the Notch agonist or HDAC inhibitor, or pharmaceutically acceptable salt thereof, are in hydrated form.
60. The composition of claim 46 , wherein the biocompatible matrix is a hydrogel.
61. The composition of claim 60 , wherein the biocompatible matrix comprises hyaluronic acid.
62. The composition of claim 46 , wherein the Notch agonist or HDAC inhibitor is SAHA, or pharmaceutically acceptable salt thereof.
63. The composition of claim 46 , wherein the Notch agonist or HDAC inhibitor is Tubastatin A, or pharmaceutically acceptable salt thereof.
64. A composition comprising:
i) a biocompatible matrix having dispersed therein:
a)
(“CHIR99021”), or a pharmaceutically acceptable salt thereof; and
b)
(“valproic acid”), or a pharmaceutically acceptable salt thereof;
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.