Use of NRF2 inducers to treat epidermolysis bullosa simplex and related diseases

• US 9,308,192 B2
• Filed: 09/12/2013
• Issued: 04/12/2016
• Est. Priority Date: 07/20/2007
• Status: Active Grant

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Coulombe, Pierre A., Kerns, Michelle L.
• Primary Examiner(s): GUDIBANDE, SATYANARAYAN R
• Application Number:
  US14/025,485
• Publication Number:
  US 20140243267A1
• Time in Patent Office: 943 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/26 Cyanate or isocyanate esters; Thiocyanate or isothiocyanate esters
• CPC Class Codes: A61K 31/275 Nitriles; Isonitriles
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 38/1825 Fibroblast growth factor [FGF]
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders

Abstract

The present invention relates to methods and compositions for the prevention and treatment of keratin-based skin diseases. In particular, the application describes compositions and methods of treating a patient suffering from skin blistering comprising the use of phase II enzyme inducers.

Claims

1. A method for treating or preventing skin blistering in a patient in need thereof or at risk of developing skin blistering, comprising administering to the patient a composition comprising a therapeutically effective amount of an Nrf2 inducer.

2. The method of claim 1, wherein the patient suffers from skin blistering.

3. The method of claim 1, wherein the Nrf2 inducer is a phase II enzyme inducer.

4. The method of claim 3, wherein the phase II inducer is an isothiocyanate.

5. The method of claim 4, wherein the phase II enzyme inducer is sulforaphane.

6. The method of claim 4, wherein the phase II enzyme inducer is a sulforaphane synthetic analogue.

7. The method of claim 6, wherein the sulforaphane synthetic analogue is exo-2-acetyl-6-isothiocyanatonorbomane.

8. The method of claim 1, wherein the Nrf2 inducer is keratinocyte growth factor.

9. The method of claim 1, wherein the Nrf2 inducer is oltipraz.

10. The method of claim 1, wherein the Nrf2 inducer is ethacrynic acid.

11. The method of claim 1, wherein the Nrf2 inducer causes the selective induction of K6, K16 or K17 in the keratinocytes in the skin of the patient.

12. The method of claim 1, wherein the composition comprising the NRF2 inducer is topically administered to the patient.

13. The method of claim 12, wherein the amount of Nrf2 inducer in the composition topically administered to the patient is from about 100 nmol/cm2 to about 1 μ

mol/cm2.

14. The method of claim 12, wherein the composition comprising the Nrf2 inducer is a topical preparation selected from the group consisting of ointment, cream, emulsion, lotion and gel.

15. The method of claim 13, wherein the composition father comprises one or more pharmaceutical, biological or molecular biological active agents.

16. The method of claim 1, wherein the patient is a mammal.

17. The method of claim 16, wherein the mammal is a human.

18. The method of claim 1, wherein the patient suffers from Epidermolysis bullosa simplex.

19. The method of claim 1, wherein the patient suffers from Epidermolysis bullosa simplex-Weber-Cockayne type, Epidermolysis bullosa simplex-Koebner type, Epidermolysis bullosa simplex with mottled pigmentation, Epidermolysis bullosa simplex-Dowling-Meara type, or Epidermolysis bullosa simplex with muscular dystrophy.

20. The method of claim 19, wherein the Epidermolysis bullosa simplex is caused by a mutation at the K14 locus.

21. The method of claim 1, wherein the Nrf2 inducer is a phase II enzyme inducer.

22. The method of claim 21, wherein the phase II inducer is an isothiocyanate.

23. The method of claim 21, wherein the phase II enzyme inducer is sulforaphane.

24. The method of claim 21, wherein the phase II enzyme inducer is a sulforaphane synthetic analogue.

25. The method of claim 24, wherein the sulforaphane synthetic analogue is exo-2-acetyl-6-isothiocyanatonorbornane.

26. The method of claim 1, wherein said skin blistering is a keratin-based skin disease.

27. The method of claim 26, wherein the keratin-based skin disease is selected from the group consisting of epidermolytic hyperkeratosis, ichtyosis bullosa of Siemens, pachyonychia congenita, epidermolytic or non-epidermolytic palmoplantar keratoderma (diffuse or focal) steatocystoma multiplex, Naegeli-Franceschetti4adessohn syndrome and dermatopathia pigmentosa reticularis.

28. The method of claim 26, wherein the disease is caused by a mutation at the K14 locus.

29. The method of claim 26, wherein the Nrf2 inducer is a phase II enzyme inducer.

30. The method of claim 29, wherein the phase II inducer is an isothiocyanate.

31. The method of claim 29, wherein the phase II enzyme inducer is sulforaphane.

32. The method of claim 29, wherein the phase II enzyme inducer is a sulforaphane synthetic analogue.

33. The method of claim 32, wherein the sulforaphane synthetic analogue is exo-2-acetyl-6-isothiocyanatonorbornane.

34. The method of claim 26, wherein the Nrf2 inducer is keratinocyte growth factor.

35. The method of claim 26, wherein the Nrf2 inducer is oltipraz.

36. The method of claim 26, wherein the Nrf2 inducer is ethacrynic acid.

37. The method of claim 26, wherein the Nrf2 inducer causes the selective induction of K6, K16 or K17 in the keratinocytes in the skin of the patient.

38. The method of claim 26, wherein the composition comprising the Nrf2 inducer is topically administered to the patient.

39. The method of claim 38, wherein the amount of Nrf2 inducer in the composition topically administered to the patient is from about 100 nmol to about 1 μ

mol/cm2.

40. The method of claim 38, wherein the composition comprising the Nrf2 inducer is a topical preparation selected from the group consisting of ointment, cream, emulsion, lotion and gel.

41. The method of claim 39, wherein the composition further comprises one or more pharmaceutical, biological or molecular biological active agents.

42. The method of claim 26, wherein the patient is a mammal.

43. The method of claim 42, wherein the mammal is a human.

44. The method of claim 15, wherein the one or more pharmaceutical, biological or molecular biological active agents comprises jojoba oil.

45. The method of claim 41, wherein the one or more pharmaceutical, biological or molecular biological active agents comprises jojoba oil.

46. The method of claim 1, further comprising identifying a patient with skin blistering or pre-disposed to developing skin blistering.

47. The method of claim 1, wherein the method comprises treating skin blistering in a patient in need thereof comprising administering to the patient a composition comprising a therapeutically effective amount of an Nrf2 inducer.