Processing

Please wait...

Settings

Settings

Goto Application

1. WO2020227642 - COMPOSITIONS FOR SKIN AND WOUNDS AND METHODS OF USE THEREOF

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

WHAT IS CLAIMED IS:

1. A method for promoting and/or improving wound healing in a human subject in need thereof, comprising intradermally or topically administering to a wound of the subject an effective amount of a pharmaceutical composition comprising a messenger RNA (mRNA) comprising an open reading frame (ORF) encoding a wound healing polypeptide.

2. A method for preventing and/or reducing scar formation at a wound in a human subject in need thereof, comprising intradermally or topically administering to the wound of the subject an effective amount of a pharmaceutical composition comprising a messenger RNA (mRNA) comprising an open reading frame (ORF) encoding a wound healing polypeptide.

3. The method of claim 1 or 2, wherein the wound is a surgical wound, a bum, an abrasive wound, a skin biopsy site, a chronic wound, an injury, a graft wound, a diabetic wound, a diabetic ulcer, a pressure ulcer, a bed sore, or combinations thereof.

4. The method of claim 3, wherein the injury is a traumatic injury wound.

5. The method of claim 3, wherein the diabetic ulcer is a diabetic foot ulcer.

6. The method of claim 1 or 2, wherein the wound is a nonhealing wound.

7. The method of claim 6, wherein the nonhealing wound is a diabetic foot ulcer, a pressure ulcer, or a chronic venous leg ulcer.

8. The method of any one of the preceding claims, wherein the wound is an open wound.

9. The method of any one of claims 1 to 7, wherein the wound is a closed wound.

10. The method of any one of claims 1 to 7, wherein the wound is an abraded wound.

11. The method of any one of the proceeding claims, wherein the subject has diabetes.

12. A method for reducing the visibility of a scar in a human subject in need thereof, comprising intradermally or topically administering to the scar of the subject an effective amount of a pharmaceutical composition comprising a messenger RNA (mRNA) comprising an open reading frame (ORF) encoding a wound healing polypeptide.

13. The method of any one of claims 1 to 12, wherein the wound healing polypeptide is selected from the group consisting of a growth factor, a cytokine, a chemokine, a protease inhibitor, and a collagen.

14. The method of claim 13, wherein the wound healing polypeptide is a growth factor selected from the group consisting of amphiregulin, connective tissue growth factor (CTGF), epidermal growth factor (EGF), epigen, epiregulin, fibroblast growth factor 2 (FGF2), fibroblast growth factor 7 (FGF7), fibroblast growth factor 10 (FGF10), heparin binding epidermal growth factor-like growth factor (HB-EGF), insulin-like growth factor 1 (IGF1), insulin-like growth factor 2 (IGF2), neuregulin 1 (NRG-1), placental growth factor (PLGF), a platelet derived growth factor (PDGF) (e g., PGDF-AA, PGDF-BB, or PGDF-AB), transforming growth factor a (TGF-a), transforming growth factor b (TGF-b), and vascular endothelial growth factor C (VEGF-C).

15. The method of claim 13, wherein the wound healing polypeptide is a cytokine selected from the group consisting of granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), hepatocyte growth factor (HGF), interleukin 1 (IL-1), interleukin 6 (IL-6), interleukin 8 (IL-8), interleukin 10 (IL-10), and tumor necrosis factor a (TNF-a).

16. The method of claim 13, wherein the chemokine is macrophage chemo-attractant protein (MCP-1) or stromal cell-derived factor 1 (SDF-1).

17. The method of claim 13, wherein the protease inhibitor is secretory leukocyte protease inhibitor (SLPI).

18. A method for treating epidermolysis bullosa in a human subject in need thereof, comprising intradermally or topically administering to a blister or skin erosion of the subject an effective amount of a pharmaceutical composition comprising a messenger RNA (mRNA) comprising an open reading frame (ORF) encoding a collagen.

19. The method of claim 13 or 18, wherein the collagen is selected from the group consisting of collagen type III, collagen type IV, collagen type V, collagen type VI, collagen type VII, collagen type VIII, collagen type XII, collagen type XIII, collagen type XIV, collagen type XVI, collagen type XVII, collagen type XVIII, collagen type XIX, and collagen type XXVIII.

20. The method of any one of claims 1 to 19, wherein the wound healing polypeptide comprises the amino acid sequence set forth in any one of SEQ ID NOs: 9-38, 45-84, 197-211, or 213-255.

21. The method of any one of claims 1 to 19, wherein the wound healing polypeptide does not comprise VEGF-A.

22. The method of any one of claims 1 to 21, comprising topically administering to the subject the effective amount of the pharmaceutical composition.

23. The method of any one of claims 1 to 21, comprising intradermally administering to the subject the effective amount of the pharmaceutical composition.

24. The method of claim 23, wherein the intradermally administering is microneedle intradermal administering.

25. The method of any one of the preceding claims, wherein the mRNA comprises a microRNA (miR) binding site.

26. The method of claim 25, wherein the microRNA is expressed in an immune cell of hematopoietic lineage or a cell that expresses TLR7 and/or TLR8 and secretes pro-inflammatory cytokines and/or chemokines.

27. The method of claim 25, wherein the microRNA binding site is for a microRNA selected from the group consisting of miR-126, miR-142, miR-144, miR-146, miR-150, miR-155, miR-16, miR-21, miR-223, miR-24, miR-27, miR-26a, or any combination thereof.

28. The method of claim 25, wherein the microRNA binding site is for a microRNA selected from the group consisting of miR126-3p, miR-142-3p, miR-142-5p, miR-155, or any combination thereof.

29. The method of claim 25, wherein the microRNA binding site is a miR-142-3p binding site.

30. The method of any one of claims 25-29, wherein the microRNA binding site is located in the 3' UTR of the mRNA.

31. The method of any one of the preceding claims, wherein the mRNA comprises a 3' UTR, said 3' UTR comprising a nucleic acid sequence at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to a 3' UTR sequence of SEQ ID NO: 111.

32. The method of any one of the preceding claims, wherein the mRNA comprises a 5' UTR, said 5' UTR comprising a nucleic acid sequence at least 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to a 5' UTR sequence of SEQ ID NO:3.

33. The method of any one of the preceding claims, wherein the mRNA comprises a 5' terminal cap.

34. The method of claim 33, wherein the 5' terminal cap comprises a CapO, Capl, ARC A, inosine, N1 -methyl-guanosine, 2'-fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, 2-azidoguanosine, Cap2, Cap4, 5' methylG cap, or an analog thereof.

35. The method of any one of the preceding claims, wherein the mRNA comprises a poly-A region.

36. The method of claim 35, wherein the poly-A region is at least about 10, at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90 nucleotides in length, or at least about 100 nucleotides in length.

37. The method of claim 35, wherein the poly-A region has about 10 to about 200, about 20 to about 180, about 50 to about 160, about 70 to about 140, or about 80 to about 120 nucleotides in length.

38. The method of any one of the preceding claims, wherein the mRNA comprises at least one chemically modified nucleobase, sugar, backbone, or any combination thereof.

39. The method of claim 38, wherein the at least one chemically modified nucleobase is selected from the group consisting of pseudouracil (y), N1 methylpseudouracil (hi ΐ y). 1-ethylpseudouracil, 2-thiouracil (s2U), 4’-thiouracil, 5-methylcytosine, 5-methyluracil, 5-methoxyuracil, and any combination thereof.

40. The method of claim 38 or 39, wherein at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or 100% of the uracils are chemically modified to 5-methoxyuracil.

41. The method of any one of the preceding claims, wherein the pharmaceutical composition further comprises a delivery agent.

42. The method of claim 41, wherein the delivery agent comprises a lipid nanoparticle.

43. The method of claim 42, wherein the lipid nanoparticle comprises:

(a) (i) Compound II, (ii) Cholesterol, and (iii) PEG-DMG or Compound I;

(b) (i) Compound VI, (ii) Cholesterol, and (iii) PEG-DMG or Compound I;

(c) (i) Compound II, (ii) DSPC or DOPE, (iii) Cholesterol, and (iv) PEG-DMG or Compound I;

(d) (i) Compound VI, (ii) DSPC or DOPE, (iii) Cholesterol, and (iv) PEG-DMG or Compound I;

(e) (i) Compound II, (ii) Cholesterol, and (iii) Compound I; or

(f) (i) Compound II, (ii) DSPC or DOPE, (iii) Cholesterol, and (iv) Compound I.