TAZ ACTIVATORS AND WNT AGONISTS FOR TREATING EAR DISORDERS

1 . A method for increasing proliferation of a cochlear supporting cell or a vestibular supporting cell, comprising contacting the supporting cell with:

a) a transcriptional coactivator with PDZ-binding motif (TAZ) activator; and

b) a Wnt agonist;

wherein (a) and (b) can occur in any order or simultaneously, thereby increasing cochlear supporting cell or vestibular supporting cell proliferation compared to a vehicle control.

2 . A method for producing an expanded population of cochlear or vestibular cells, comprising contacting a population of cochlear supporting cells or vestibular supporting cells with:

a) a transcriptional coactivator with PDZ-binding motif (TAZ) activator and;

b) a Wnt agonist

wherein (a) and (b) can occur in any order or simultaneously, thereby producing an expanded population of cochlear or vestibular cells compared to a vehicle control.

3 . The method of any preceding claim, further comprising contacting the cochlear or vestibular supporting cell(s) with an epigenetic agent.

4 . The method of claim 3 , wherein the epigenetic agent is an HDAC inhibitor, an EZH2 inhibitor, a DOT1L inhibitor a KDM inhibitor, or an LSD1 inhibitor.

5 . The method of claim 1 or claim 2 , wherein the cochlear supporting cell(s) or vestibular supporting cell(s) express(es) leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5).

6 . The method of any preceding claim, wherein the cochlear supporting cell(s) or vestibular supporting cell(s) is/are a mature cell(s).

7 . The method of any of claims 2 - 4 , wherein the expanded population of cochlear or vestibular cells expresses leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5).

8 . The method of any preceding claim, wherein the TAZ activator in combination with the Wnt agonist increases Lgr5 Activity of the expanded population of cochlear or vestibular cells by a factor of at least 10, 20, 30, 40, 50, 75, 100 or 200% compared to a Wnt agonist alone or a Wnt agonist in combination with valproic acid, wherein the Lgr5 Activity is measured in a Stem Cell Proliferation Assay

9 . 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 transcriptional coactivator with PDZ-binding motif (TAZ) activator; and

b) a Wnt agonist wherein (a) and (b) can occur in any order or simultaneously.

10 . The method of claim 9 , wherein the subject has an inner ear hearing or balance disorder.

11 . The method of any of claims 9 - 10 , wherein the inner ear hearing or balance disorder is sensorineural hearing loss.

12 . The method of any of claims 9 - 11 , wherein the treatment results in improved auditory function when assessed by behavioural audiometry or auditory brainstem response (ABR) testing.

13 . The method of any preceding claim, wherein the TAZ activator is IBS008738, TM-25659, FHZ-000706, or TT10.

14 . The method of any preceding claim, wherein the Wnt agonist is a GSK3 inhibitor.

15 . The method of any one of claims 9 - 14 , further comprising administering to the subject, an epigenetic agent.

16 . The method of claim 15 , wherein the epigenetic agent is an HDAC inhibitor, an EZH2 inhibitor, a DOT1L inhibitor a KDM inhibitor or an LSD1 inhibitor.

17 . The method of claim 16 , wherein the HDAC inhibitor is Valproic Acid (VPA)

18 . The method of claim 16 , wherein the EZH2 inhibitor is selected from the group consisting of; CPI-1205, CPI-169, E11, PF-06821497, tazemetostat, valemetostat, CPI-360, EPZ011989, UNC 2399, and PF 06726304.

19 . The method of claim 16 , wherein the KDM inhibitor is AS 8351, TC-E 5002 or EPT-103182.

20 . The method of claim 16 , wherein the LSD1 inhibitor is selected from the group consisting of GSK-2879552, GSK-LSD1, Tranylcypromine, Phenelzine sulfate, ORY-1001, and RN-1.

21 . The method of claim 16 , wherein the DOT1L inhibitor is selected from the group consisting of EPZ004777, pinometostat and SGC0946.

22 . The method of any preceding claim, wherein the TAZ activator is administered locally and/or systemically.

23 . The method of any preceding claim, wherein the Wnt agonist is administered locally and/or systemically.

24 . The method of any preceding claim, wherein the epigenetic agent is administered locally and/or systemically.

25 . The method of any of claims 22 - 24 , wherein the local administration is to the tympanic membrane, the middle ear or the inner ear.

26 . The method of any of claims 22 - 25 , wherein the systemic administration is oral or parenteral.

27 . The method of any of claims 22 - 26 , wherein the TAZ activator is IBS008738, TM-25659, FHZ-00706-1, or TT10.

28 . A pharmaceutical composition comprising a TAZ activator, a Wnt agonist and a pharmaceutically acceptable carrier.

29 . The pharmaceutical composition of claim 28 , wherein the TAZ activator is IBS008738, TM-25659, FHZ-000706, or TT10.

30 . The pharmaceutical composition of any of claims 28 - 29 , wherein the Wnt agonist is a GSK3 inhibitor.

31 . The pharmaceutical composition of claim 30 , wherein the GSK3 inhibitor is selected from the group consisting of: AZD1080, LY2090314, a substituted 3-Imidazo[1,2-a]pyridin-3-yl-4-(1,2,3,4-tetrahydro-[1,4]diazepino-[6,7,1-hi]indol-7-yl)pyrrole-2,5-dione, GSK3 inhibitor XXII or CHIR99021.

32 . The pharmaceutical composition of any of claims 28 - 31 further comprising further comprising an epigenetic agent.

33 . The pharmaceutical composition of claim 32 , wherein the epigenetic agent is an HDAC inhibitor, an EZH2 inhibitor, a DOT1L inhibitor a KDM inhibitor or a LSD1 inhibitor.

34 . The pharmaceutical composition of claim 33 , wherein the HDAC inhibitor is Valproic Acid (VPA)

35 . The pharmaceutical composition of claim 33 , wherein the EZH2 inhibitor is selected from the group consisting of: CPI-1205, CPI-169, E11, PF-06821497, tazemetostat, valemetostat, CPI-360, EPZ011989, UNC 2399, and PF 06726304.

36 . The pharmaceutical composition of claim 33 , wherein the DOT1L inhibitor is selected from the group consisting of EPZ004777, pinometostat, and SGC0946.

37 . The pharmaceutical composition of claim 33 , wherein the KDM inhibitor is selected from the group consisting of AS 8351, TC-E 5002 and EPT-103182.

38 . The pharmaceutical composition of claim 33 , wherein the LSD1 inhibitor is selected from the group consisting of GSK-2879552, GSK-LSD1, Tranylcypromine, Phenelzine sulfate, RN-1, and ORY-1001.

39 . The pharmaceutical composition of any of claims 28 - 38 , wherein the pharmaceutical composition is in a biocompatible matrix.

40 . The pharmaceutical composition of claim 39 , wherein the biocompatible matrix comprises 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, glycerol monooleate, silk materials, or a combination thereof.

41 . The pharmaceutical composition of any of claims 28 - 40 , wherein the pharmaceutical composition is formulated for systemic and/or local administration.

42 . The pharmaceutical composition any of claims 28 - 41 , for use in treating or preventing an inner ear hearing or balance disorder.

43 . The pharmaceutical composition for use according to claim 42 , wherein the inner ear hearing or balance disorder is sensorineural hearing loss.

44 . Use of the pharmaceutical composition of any of claims 28 - 43 in the manufacture of a medicament for the treatment or prevention of an inner ear hearing or balance disorder.

45 . Use of the pharmaceutical composition according to claim 44 , wherein the inner ear hearing or balance disorder is sensorineural hearing loss.

46 . A transcriptional coactivator with PDZ-binding motif (TAZ) activator for use in treating or preventing an inner ear hearing or balance disorder in a subject, wherein the subject has been, or will be, administered a Wnt agonist.

47 . A Wnt agonist for use in treating or preventing an inner ear hearing or balance disorder in a subject, wherein the subject has been, or will be, administered a transcriptional coactivator with PDZ-binding motif (TAZ) activator.

48 . An epigenetic agent for use in treating or preventing an inner ear hearing or balance disorder in a subject, wherein the subject has been, or will be, administered a transcriptional coactivator with PDZ-binding motif (TAZ) activator and a Wnt agonist.

49 . The TAZ activator, Wnt agonist or epigenetic agent for use according to any of claims 43 - 47 , wherein the inner ear hearing or balance disorder is sensorineural hearing loss.

50 . The TAZ activator, Wnt agonist or epigenetic agent for use according to any of claims 44 - 49 , wherein the treatment is as defined in any of claims 9 - 26 .

51 . A container comprising a transcriptional coactivator with PDZ-binding motif (TAZ) activator and instructions, where those instructions describe the TAZ activator use for treating or preventing an inner ear hearing or balance disorder in a subject, wherein the instructions require that the subject has been, or will be, administered a Wnt agonist.

52 . A container comprising a Wnt agonist and instructions, where the instructions describe the Wnt agonist's use in treating or preventing an inner ear hearing or balance disorder in a subject, wherein the instructions require that the subject has been, or will be, administered a transcriptional coactivator with PDZ-binding motif (TAZ) activator.

53 . A container comprising an epigenetic agent and instructions, where those instructions describe the epigenetic agent's use in treating or preventing an inner ear hearing or balance disorder in a subject, and wherein the instructions require that the subject has been, or will be, administered a transcriptional coactivator with PDZ-binding motif (TAZ) activator and a Wnt agonist.

54 . The container according to any of claims 51 - 53 , wherein the inner ear hearing or balance disorder is sensorineural hearing loss.

55 . The container according to any of claims 51 - 53 , wherein the treatment is as defined in any of claims 9 - 26 .