Retinoid-liposomes for treating fibrosis
What is described are pharmaceutical compositions comprising a double-stranded nucleic acid molecule comprising a sense strand and an antisense strand wherein the sense and antisense strands are selected from the oligonucleotides described as SERPINH1_2 (SEQ ID NOS: 60 and 127), SERPINH1_45a (SEQ ID NOS: 98 and 165), and SERPINH1_51 (SEQ ID NOS: 101 and 168), and drug carrier comprising a mixture of a retinoid and a lipid vesicle, and methods of using these pharmaceutical compositions to treat a disease associated with hsp47 expression, including fibrosis.
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 comprising a drug carrier and a double-stranded nucleic acid molecule, wherein the drug carrier comprises a liposome and a stellate cell-specific amount of diVA-PEG-diVA, and wherein the double-stranded nucleic acid molecule comprises the structure (A1) set forth below:
5′(N) x —Z3′(antisense strand)
3′Z′—(N′) y - z″ 5′(sense strand) (A1)
wherein each of N and N′ is a 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 next N or N′ by a covalent bond;
wherein each of Z and Z′ is independently present or absent, but if present independently includes 1-5 consecutive nucleotides or non-nucleotide moieties or a combination thereof covalently attached at the 3′-terminus of the strand in which it is present;
wherein z″ may be present or absent, but if present is a capping moiety covalently attached at the 5′-terminus of (N′) y ;
wherein each of x and y is independently an integer between 18 and 40;
wherein (N) x comprises an antisense sequence to the mRNA coding sequence for human hsp47 exemplified by SEQ ID NO:1 wherein the composition reduces expression of hsp47.
2. The method according to claim 1 , wherein the pharmaceutical formulation 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 fibrosis cardiomyopathy, atherosclerosis (Bergers disease, etc), 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 of skin fibrosis including scleroderma, keloids and hypertrophic scars scleroderma; 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; myleoid leukemia; acute myelogenous leukemia; myelodysplastic syndrome; lymphangiolyomyositosis (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.