Use of cyclosporine analogues for treating fibrosis
Disclosed herein include methods, compositions, and kits suitable for use in preventing, treating or reverse fibrosis. The methods comprise administering to a subject in need thereof a composition comprising a cyclosporine analogue (for example, CRV431), or a pharmaceutically acceptable salt, solvate, stereoisomer thereof. The compositions and kits comprise a cyclosporine analogue (for example, CRV431), or a pharmaceutically acceptable salt, solvate, stereoisomer thereof.
1. A method for reducing production of extracellular matrix (ECM) molecules in a subject having fibrosis or at risk of developing fibrosis, the method comprising: selecting a composition to reduce the production of the ECM molecules in the subject, the composition comprising:
and contacting at least one fibroblastic cell of the subject with an effective dose of the composition.
2. The method of claim 1 , wherein the subject is suffering from fibrosis.
3. The method of claim 1 , comprising inhibiting fibrosis formation in the subject.
4. The method of claim 1 , wherein the fibrosis is non-liver fibrosis.
5. The method of claim 1 , wherein the fibrosis is liver fibrosis.
6. The method of claim 5 , wherein the liver fibrosis is cirrhosis or non-alcoholic steatohepatitis (NASH).
7. The method of claim 6 , wherein the cirrhosis is associated with viral hepatitis, schistosomiasis and chronic alcoholism.
8. The method of claim 1 , wherein the fibrosis is induced by a therapeutic agent, an injury, or a combination thereof.
9. The method of claim 1 , comprising reducing fibrosis formation in the subject by at least 5%, 10%, 20%, 50%, 70%, 90%, or more as compared to untreated subjects.
10. The method of claim 1 , comprising delaying fibrosis formation in the subject as compared to untreated subjects.
11. The method of claim 1 , further comprising contacting the fibroblastic cell with one or more additional therapeutic agents.
12. The method of claim 11 , wherein the one or more additional therapeutic agents comprise an additional antifibrotic agent or an anti-inflammatory agent.
13. The method of claim 1 , further comprising after the contacting, measuring the expression of one or more biomarker genes selected from the group consisting of: Endothelial Cell Specific Molecule 1 (ESM1), Nuclear Receptor Coactivator 3 (NCOA3), Interferon Induced Protein 44 Like (IFI44L), MicroRNA 194-2 (mIR-194-2), Dickkopf WNT Signaling Pathway Inhibitor 1 (DKK1), Lysyl Oxidase Like 2 (LOXL2), Ubiquitin D/Human leukocyte antigen (HLA)-F adjacent transcript 10 (UBD/FAT10), STRA6 Signaling Receptor And Transporter Of Retinol (STRA6), RCC1 Domain Containing 1 (RCCD1), and Dual Oxidase 2 (DUOX2).
14. The method of claim 1 , further comprising after the contacting, measuring secretion of one or more markers selected from monocyte chemoattractant protein (MCP-1), interleukin-6 (IL-6), matrix metalloproteinase-7 (MMP-7), tissue inhibitor of metalloproteinase-1 (TIMP1), hyaluronic acid, and collagen 1α1.
15. The method of claim 1 , wherein the effective dose has a dose concentration ranging from 0.2 μM to 5 μM.
16. The method of claim 1 , wherein the effective dose comprises an effective daily dose of CRV431 at from 10 mg to 250 mg.
17. The method of claim 1 , wherein the fibroblast cell is selected from the group consisting of lung fibroblasts, cardiac fibroblasts, dermal fibroblasts, renal mesangial cells, and hepatic stellate cells.
18. A method for reducing non-liver fibrosis or reversing non-liver fibrosis in a subject having non-liver fibrosis, the method comprising:
administering to the subject having non-liver fibrosis a pharmaceutically effective amount of a composition comprising:
thereby reducing the non-liver fibrosis or reversing the non-liver fibrosis by reducing the production of extracellular matrix molecules.
19. The method of claim 18 , wherein the non-liver fibrosis is pulmonary fibrosis or scleroderma.