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1. WO2020163814 - COMPOSITIONS ET PROCÉDÉS POUR GÉNÉRER DES CELLULES CILIÉES PAR INHIBITION DE CIBLES ÉPIGÉNÉTIQUES

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[ EN ]

We Claim:

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

a) a first epigenetic agent; 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 first epigenetic agent 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 claim 1 or 2, further comprising cochlear supporting cell or a vestibular supporting cell with: c) a second epigenetic agent wherein (a), (b) or (c) can occur in any order or simultaneously, thereby increasing cochlear supporting cell or vestibular supporting cell proliferation compared to a vehicle control.

4. The method of any preceding claim, wherein

a) the first epigenetic agent epigenetic agent is a lysine specific demethylase 1 (LSD1) inhibitor, an enhancer of zeste homolog 2 (EZH2) inhibitor, a disruptor of telomeric silencing 1-like (DOT1L) inhibitor, or a histone lysine demethylase (KDM) inhibitor; and

b) the second epigenetic agent is an HDAC inhibitor, an LSD1 inhibitor, an EZH2 inhibitor, a DOT1L inhibitor a or KDM inhibitor.

5. The method of any preceding claim, 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) are/is a mature cell(s).

7. The method of any preceding claim, 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 epigenetic agent in combination with the Wnt agonist increases the 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 first epigenetic agent ; and

b) a Wnt agonist

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

10. The method of claim 9, further comprising administering to the subject :c) a second epigenetic agent wherein (a), (b) or (c) can occur in any order or simultaneously.

11. The method of claim 9 or 10, wherein a) the first epigenetic agent epigenetic agent is a lysine specific demethylase 1 (LSD1) inhibitor, an enhancer of zeste homolog 2 (EZH2) inhibitor, a disrupter of telomeric silencing 1-like (DOT1L) inhibitor, or a histone lysine demethylase (KDM) inhibitor; and

b) the second epigenetic agent is an HDAC inhibitor, an LSD1 inhibitor, an EZH2 inhibitor, a DOT1L inhibitor a or KDM inhibitor.

12. The method of any of claims 9-11, wherein the subject has an inner ear hearing or balance disorder.

13. The method of any of claims 12, wherein the inner ear hearing or balance disorder is sensorineural hearing loss.

14. The method of any of claims 9-13, wherein the treatment results in improved auditory function when assessed by behavioural audiometry or auditory brainstem response (ABR) testing.

15. The method of any preceding claim, wherein the epigenetic agent is an LSD1 inhibitor selected from the group consisting of GSK-2879552, GSK-LSD1, Tranylcypromine, Phenelzine sulfate, RN-1, and ORY-1001.

16. The method of any preceding claim, wherein the epigenetic agent is an EZH2 inhibitor selected from the group consisting of: CPI-1205, CPI-169, CPI-360, EPZ011989, El1, PF-06821497, UNC 2399, tazemetostat, valemetostat, and PF 06726304.

17. The method of any preceding claim, wherein the wherein the epigenetic agent is a DOT1L inhibitor selected from the group consisting of EPZ004777, pinometostat and SGC0946.

18. The method of any preceding claim, wherein the wherein the epigenetic agent is KDM inhibitor is selected from the group consisting AS 8351, EPT 103182, and TC-E 5002.

19. The method of any claims 3-18, wherein the second epigenetic is an HDAC inhibitor that is Valproic Acid (VPA)

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

21. The method of claim 20, 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.

22. The method of any preceding claim, wherein the epigenetic agent 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 of claims 22-23, w'herein the local administration is to the tympanic membrane, the middle ear or the inner ear.

25. The method of claim 24, wherein the local administration is to the middle ear.

26. The method of any of claims 22-23, wherein the systemic administration is oral or parenteral.

27. A pharmaceutical composition comprising a first epigenetic agent, a Wnt agonist, and a pharmaceutically acceptable carrier.

28. The pharmaceutical composition of claim 27, further a second epigenetic agent.

29. The pharmaceutical composition of claim 27 or 28, wherein:

a) the first epigenetic agent epigenetic agent is a lysine specific demethylase 1 (LSD1) inhibitor, an enhancer of zeste homolog 2 (EZH2) inhibitor, a disrupter of telomeric silencing 1-like (DOT1L) inhibitor, or a histone lysine demethylase (KDM) inhibitor; and

b) the second epigenetic agent is an HDAC inhibitor, an LSD1 inhibitor, an EZH2 inhibitor, a DOT1L inhibitor a or KDM inhibitor.

30. The pharmaceutical composition of any of claims 27-29, wherein the epigenetic agent is an LSD1 inhibitor selected from the group consisting of GSK-2879552, GSK-LSD1, RN- 1, Tranylcypromine , Phenelzine sulfate, and ORY-1001.

31. The pharmaceutical composition of any of claims 27-29, wherein the epigenetic agent is EZH2 inhibitor selected from the group consisting of: CPI-1205, CPI-169, CPI-360, EPZ011989, El1, PF-06821497, UNC 2399, tazemetostat, valemetostat, PF06726304.

32. The pharmaceutical composition of any of claims 27-29, wherein the wherein the epigenetic agent is a DOT1L inhibitor selected from the group consisting of EPZ004777, pinometostat and SGC0946.

33. The pharmaceutical composition of any of claims 27-29, wherein the wherein the epigenetic agent is KDM inhibitor is selected from the group consisting AS 8351, EPT 103182, and TC-E 5002.

34. The pharmaceutical composition of any of claims 27-29, wherein the second epigenetic is an HDAC inhibitor that is Valproic Acid (VPA).

35. The pharmaceutical composition of any of claims 27-34, wherein the Wnt agonist is a GSK3 inhibitor.

36. The pharmaceutical composition of claim 35, 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.

37. The pharmaceutical composition of any of claims 27-36, wherein the pharmaceutical composition is in a biocompatible matrix.

38. The pharmaceutical composition of claim 38, 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.

39. The pharmaceutical composition of any of claims 27-38, wherein the pharmaceutical composition is formulated for local or systemic administration.

40. The pharmaceutical composition any of claims 27-39 for use in treating or preventing an inner ear hearing or balance disorder.

41. The pharmaceutical composition for use according to claim 40, wherein the inner ear hearing or balance disorder is sensorineural hearing loss.

42. Use of the pharmaceutical composition of any of claims 27-41 in the manufacture of a medicament for the treatment or prevention of an inner ear hearing or balance disorder.

43. A container comprising an epigenetic agent and instructions, where those instructions describe the epigenetic agent’s 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.

44. A container comprising a Wnt agonist and instructions, where those 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 an epigenetic agent.

45. 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, wherein the instructions require that the subject has been, or will be, administered an epigenetic agent and a Wnt agonist.

46. The container according to any of claims 43-45, wherein the inner ear hearing or balance disorder is sensorineural hearing loss.