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