Method for treating fibrosis using siRNA and a retinoid-lipid drug carrier

Patent metadata

Field	Value
Publication number	US-9456984-B2
Application number	US-201414294021-A
Country	US
Kind code	B2
Filing date	Jun 2, 2014
Priority date	Jun 8, 2011
Publication date	Oct 4, 2016
Grant date	Oct 4, 2016

Abstract

What is described is a method for treating a fibrotic disease by administering a pharmaceutical composition comprising a drug carrier, which comprises a lipid and a retinoid, and a double-stranded nucleic acid molecule, which comprises an antisense sequence to mRNA encoding human hsp47.

First claim

What is claimed:

1. A method for treating a fibrotic disease in a subject in need thereof, the method comprising administering an effective amount of a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a drug carrier and a double-stranded nucleic acid molecule, wherein the drug carrier comprises a lipid and a retinoid, wherein the lipid comprises a permanent cationic lipid or an ionizable cationic lipid, and wherein the double-stranded nucleic acid molecule comprises the structure (A2):

(A2) 5′ N1-(N)x - Z 3′ (antisense strand)

     3′ Z′-N2-(N′)y -z″ 5′ (sense strand)

wherein each of N 2 , N and N′ is an unmodified or modified ribonucleotide, or an unconventional moiety;
wherein each of (N) x and (N′) y is an oligonucleotide in which each consecutive N or N′ is joined to the adjacent N or N′ by a covalent bond;
wherein each of x and y is independently an integer between 17 and 39;
wherein the sequence of (N′) y has complementarity to the sequence of (N) x and (N) x has complementarity to a consecutive sequence in a target RNA;
wherein N 1 is covalently bound to (N) x and is mismatched to the target RNA or is a complementary DNA moiety to the target RNA;
wherein N 1 is a natural or modified uridine, deoxyribouridine, ribothymidine, deoxyribothymidine, adenosine or deoxyadenosine;
wherein z″ may be present or absent, but if present is a capping moiety covalently attached at the 5′-terminus of N 2 —(N′) y ;
wherein each of Z and Z′ is independently present or absent, but if present is independently 1-5 consecutive nucleotides, consecutive non-nucleotide moieties or a combination thereof covalently attached at the 3′-terminus of the strand in which it is present; and
wherein (N) x comprises an antisense sequence to the mRNA coding sequence for human hsp47 exemplified by SEQ ID NO:1.

2. The method according to claim 1 , wherein the pharmaceutical composition is parenterally administered.

3. The method of claim 1 , wherein the fibrotic disease is liver fibrosis.

4. The method of claim 3 , wherein liver fibrosis consists of non-alcoholic steatohepatitis; hepatitis; hepatic fibrosis; chronic hepatitis C virus infection; hepatic cirrhosis; chronic hepatic damage; or liver cancer.

5. The method of claim 1 , wherein the fibrotic disease is pulmonary fibrosis.

6. The method of claim 5 , wherein the pulmonary fibrosis consists of pulmonary fibrosis including idiopathic pulmonary fibrosis, interstitial lung disease, radiation pneumonitis leading to pulmonary fibrosis; or fibrotic lung disease.

7. The method of claim 1 , wherein the fibrotic disease is kidney fibrosis.

8. The method of claim 7 , wherein the kidney fibrosis is chronic renal failure or diabetic nephropathy.

9. The method of claim 1 , wherein the fibrotic disease is peritoneal fibrosis.

10. The method of claim 9 , wherein the peritoneal fibrosis is peritoneal sclerosis associated with continual ambulatory peritoneal dialysis.

11. The method of claim 1 , wherein the fibrotic disease is pancreatic fibrosis.

12. The method of claim 11 , wherein the pancreatic fibrosis consists of pancreatitis, pancreatic fibrosis, or pancreatic cancer.

13. The method of claim 1 , wherein the fibrotic disease is cardiac fibrosis.

14. The method of claim 13 , wherein the cardiac fibrosis consists of myocardial fibrosiscardiomyopathy, atherosclerosis, endomyocardial fibrosis, atrial fibrillation, or scarring post-myocardial infarction.

15. The method of claim 1 , wherein the fibrotic disease is intestinal fibrosis.

16. The method of claim 1 , wherein the fibrotic disease is fibrosis of the eye.

17. The method of claim 16 , wherein the fibrosis of the eye consists of ocular scarring including proliferative vitreoretinopathy (PVR) or scarring resulting from surgery to treat cataract or macular degeneration, glaucoma, Grave's ophthalmopathy; ocular cicatricial pemphigoid, or drug induced ergotism.

18. The method of claim 1 , wherein the fibrotic disease is skin fibrosis.

19. The method of claim 18 , wherein the skin fibrosis consists scleroderma, keloids, hypertrophic scars, psoriasis, or Kaposi's sarcoma.

20. The method of claim 1 , wherein the fibrotic disease is fibrosis of bone.

21. The method of claim 20 , wherein the fibrosis of bone consists of myelofibrosis; myeloid leukemia; acute myelogenous leukemia; myelodysplastic syndrome; lymphangioleiomyomatosis (LAM), chronic graft vs. host disease, polycythemia vera, essential thrombocythemia, or myeloproferative syndrome.

22. The method of claim 1 , wherein the fibrotic disease is inflammatory bowel disease of variable etiology.

23. The method of claim 1 , wherein the fibrotic disease is glioblastoma in Li-Fraumeni syndrome or sporadic glioblastoma.

24. The method of claim 1 , wherein the fibrotic disease is gynecological cancer.

25. The method of claim 1 , wherein the fibrotic disease is Hansen's disease.

26. The method of claim 1 , wherein the fibrotic disease is collagenous colitis.

27. The method of claim 1 , wherein the fibrotic disease is fibrillogenesis.

28. The method of claim 1 , wherein the fibrotic disease is fibrosis of vocal cords.

29. The method of claim 28 , wherein the fibrosis of vocal cords consists of vocal cord scarring, vocal cord mucosal fibrosis, or laryngeal fibrosis.

30. The method of claim 1 , wherein the retinoid is at least partially exposed on the exterior of the drug carrier before the drug carrier reaches a stellate cell.

31. The method of claim 1 , wherein the drug carrier comprises a retinoid in the form of a retinoid-PEG conjugate.

32. The method of claim 1 , wherein the drug carrier comprises a polymer micelle, a liposome, an emulsion, a microsphere, or a nanosphere.

33. The method of claim 1 , wherein the drug carrier comprises a lipid vesicle comprising a bilayer of lipid molecules.

34. The method of claim 33 , wherein the retinoid is 0.2 wt % to 20 wt % of the lipid molecules.

35. The method of claim 33 , wherein the double-stranded nucleic acid molecule is exposed on an exterior surface of the lipid vesicle.

36. The method of claim 33 , wherein the double-stranded nucleic acid molecule is encapsulated by the lipid vesicle.

37. The method of claim 36 , wherein the double-stranded nucleic acid molecule is resistant to nucleases.

38. The method of claim 1 , wherein one strand of the double-stranded nucleic acid molecule comprises SEQ ID NO:127 and the second strand comprises SEQ ID NO:60.

39. The method of claim 38 , wherein the antisense strand comprises SEQ ID NO:127, and the sense strand comprises SEQ ID NO:60.

40. The method of claim 39 , wherein the antisense strand further comprises a 2′-O-methy

Assignees

• Nitto Denko Corp

Inventors

• Niitsu Yoshiro
• Knopov Victor
• Payne Joseph E
• Witte Richard P
• Ahmadian Mohammad
• Perelman Loren A
• Akopian Violetta
• Tanaka Yasunobu
• Feinstein Elena
• Avkin-Nahum Sharon
• Kalinski Hagar
• Mett Igor
• Minomi Kenjiro
• Ying Wenbin
• Liu Yun

Classifications

• A61P31/14

  for RNA viruses · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P27/02

  Ophthalmic agents · CPC title