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(12) Patent Application Publication (10) Pub. No.: US 2011/001412.6 A1 Evans Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2011/001412.6 A1 Evans Et Al US 2011 0014126A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/001412.6 A1 Evans et al. (43) Pub. Date: Jan. 20, 2011 (54) USE OF VITAMIND RECEPTORAGONISTS (60) Provisional application No. 60/985,972, filed on Nov. AND PRECURSORS TO TREAT FIBROSS 6, 2007. (76) Inventors: Ronald M. Evans, La Jolla, CA Publication Classification (US); Michael Downes, San Diego, CA (US); Christopher Liddle, (51) Int. Cl. New South Wales (AU): A 6LX 3/59 (2006.01) Nanthakumar Subramaniam, A6IPL/I6 (2006.01) New South Wales (AU); Caroline CI2O 1/02 (2006.01) Flora Samer, Geneva (CH) A61R 49/00 (2006.01) CI2N 5/071 (2010.01) Correspondence Address: (52) U.S. Cl. ............. 424/9.2: 514/167; 435/29: 435/375 KLARQUIST SPARKMAN, LLP 121 S.W. SALMONSTREET, SUITE 1600 (57) ABSTRACT PORTLAND, OR 97204 (US) This application relates to methods of treating, preventing, (21) Appl. No.: 12/772,981 and ameliorating fibrosis, such as fibrosis of the liver. In particular, the application relates to methods of using a vita (22) Filed: May 3, 2010 min D receptor agonist (Such as vitamin D. Vitamin Dana logs, vitamin D precursors, and vitamin D receptor agonists Related U.S. Application Data precursors) for the treatment of liver fibrosis. Also disclosed (63) Continuation-in-part of application No. 12/266,513, are methods for screening for agents that treat, prevent, and filed on Nov. 6, 2008. ameliorate fibrosis. Stellate Cells Liver RR1,3 AR, ERa ERR1,2,3, AR, ERa CNF GR, MR CNF RARa, GR, MR NF4g Rab NF4ag RARa,b, NOR1 a, RH1 TRa,b WDR NURR1 NOR1 RORa,b,g RORag CAR Receptor SF-1 FXRa,b FXRa,b epissertoup. TFIII LXRa,b PPARagd Reverba,b PPARagd COUP-TF1,I,III PXR SHP RXRa,b Reverba RXRa,b,g TR2, 4 SHP TR2, 4 Not Expressed Not Expressed CAR PNR Dax PR DaX1 PXR ER RORb ERb PR NGFb SF ERRb Reverbb NURR1 TX HNF4a RXRg PNR WDR LRH1 TLX NGFb Patent Application Publication Jan. 20, 2011 Sheet 2 of 19 US 2011/001412.6 A1 aan Patent Application Publication Jan. 20, 2011 Sheet 3 of 19 US 2011/001412.6 A1 an CN CD - s É . %.% as > 1. 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Cy Yom d uOSsedXe eNee Zs uOSSeidxe enee Patent Application Publication Jan. 20, 2011 Sheet 12 of 19 US 2011/001412.6 A1 Patent Application Publication Jan. 20, 2011 Sheet 13 of 19 US 2011/001412.6 A1 |008 09 000€ 002|| 007 Patent Application Publication Jan. 20, 2011 Sheet 14 of 19 US 2011/001412.6 A1 SAT+£GGE'| LetyzdÅO s SdT+COGZ"| O| Patent Application Publication Jan. 20, 2011 Sheet 15 of 19 US 2011/001412.6 A1 Patent Application Publication Jan. 20, 2011 Sheet 16 of 19 US 2011/001412.6 A1 e o a 0 or e o e o 0. i. i. WN OuO eNISOd 195) Olu Oo () G) 3- N m D E A (9 - O u O O m u (S O O E C) E C o E o Patent Application Publication Jan. 20, 2011 Sheet 17 of 19 US 2011/001412.6 A1 UO3nOU po Patent Application Publication Jan. 20, 2011 Sheet 18 of 19 US 2011/001412.6 A1 CY) o s UO3nOU OIO Patent Application Publication Jan. 20, 2011 Sheet 19 of 19 US 2011/001412.6 A1 CY o GN y tioissélaxe WNU. Ot/NH US 2011/0014126 A1 Jan. 20, 2011 USE OF VITAMIND RECEPTORAGONSTS that respond in a similar manner, including but not limited to AND PRECURSORS TO TREAT FIBROSS pancreatic stellate cells and renal mesangial cells. 0007. It is also unexpectedly shown herein that in the CROSS REFERENCE TO RELATED presence of the profibrotic molecule transforming growth APPLICATIONS factor-beta 1 (TGF-3), hepatocytes are also capable of responding to compounds that bind to and activate the Vita 0001. This application is a continuation-in-part of U.S. min D receptor, through induced expression of vitamin D application Ser. No. 12/266,513 filed Nov. 6, 2008, which receptor. On the basis of this observation, it is proposed that claims priority to U.S. Provisional Application No. 60/985, VDR signaling in hepatocytes acts as a Survival and differen 972 filed Nov. 6, 2007, both hereinincorporated by reference. tiation factor for these cells in the face of injury where TGF f is produced in the local hepatic micro environment. For ACKNOWLEDGMENT OF GOVERNMENT example, when liver injury occurs TGF-?3 is produced from SUPPORT the non-parenchymal cells of the liver (e.g., Kupffer cells) 0002 Aspects of this invention were made with United and possibly inflammatory cells recruited from the circula States government support under grant no. DK062434-05 tion. The relevance of these observations to hepatic fibrosis is from the National Institutes of Health (NIH), and grant nos. that vitamin D receptor ligands and their precursors will act to 402493 and 512354 from the National Health and Medical attenuate liver injury, and therefore facilitate the wound heal Research Council of Australia (NHMRCA). The United ing response, by acting to preserve liver function by promot States and Australian governments have certain rights in the ing Survival of hepatocytes, the predominant cell type com invention. prising the liver. 0008 Thus, one embodiment of the disclosure is a method of treating liver fibrosis in a subject. The method can include FIELD administeringatherapeutically effective amount of vitamin D 0003. This application relates to methods of treating, pre receptor agonist (such as 1C.25 dihydroxyvitamin D, venting, and ameliorating fibrosis, such as fibrosis of the liver. (1.O.25-(OH)-D3) or a precursor thereof, a vitamin Danalog, In particular, the application relates to methods of using a a vitamin D receptor ligand, or a vitamin D receptor agonist vitamin D receptor (VDR) agonist for the treatment, preven precursor), to a Subject having a fibrosis or at risk for devel tion, and amelioration of hepatic apoptosis, cell death or liver oping fibrosis, thereby treating the liver fibrosis. In some damage (such as liver fibrosis) and thus provide a way to examples, hepatocytes of the liver are exposed to therapeuti preserve liver function. cally effective amounts of TGF-B (for example in an amount sufficient to induce VDR expression), such as TGF-B pro BACKGROUND duced by the liver during fibrogenesis or by administering TGF-B to the subject. 0004 Hepatic fibrosis, the accumulation of abnormal 0009. The foregoing and other objects and features of the extracellular matrix (ECM) proteins and a resultant loss of disclosure will become more apparent from the following liver function, is an accompaniment of an inflammation detailed description, which proceeds with reference to the driven wound healing process triggered by chronic liver accompanying figures. injury. The main causes of liver injury leading to fibrosis in Western societies include chronic hepatitis C virus (HCV) BRIEF DESCRIPTION OF THE DRAWINGS infection, alcohol abuse, chronic hepatitis B (HBV) infection, iron overload as occurs in hereditary hemochromatosis, and 0010 FIGS. 1A and B are a series of graphs showing increasingly, non-alcoholic steatohepatitis (NASH). The expression patterns of nuclear hormone receptors (NHRs). inflammatory process ensuing from hepatic injury triggers a FIG. 1A shows a comparison of NHR family expression in variety of cellular responses including cell repair, hepatocyte murine liver and isolated primary HSCs. FIG. 1B shows a regeneration, increased extracellular matrix turnover, and quantitative comparison of VDR and SF-1 expression. The ultimately in some patients significant fibrosis. Progressive left panels show the expression of mVDR and mSF-1 in fibrosis of the liver eventually can result in cirrhosis, portal murine liver and primary isolated HSCs, and the right panels hypertension, liver failure, and hepatocelluar carcinoma. show the decrease in expression of rat VDR and SF-1 in 0005 Given the foregoing, it would be desirable to have primary HSCs observed after 1, 2 and 8 days in culture methods of treating, preventing, and ameliorating fibrosis, (normalized to the ribosomal 36B4 expression). such as fibrosis of the liver. 0011 FIGS. 2A-C is a set of digital images showing VDR expression in primary rat HSC and in human LX-2 cell line. SUMMARY (A) 20g of whole cell extracts from day 0 and day 3 rat HSCs were analyzed by western immunoblot analysis using a VDR 0006. Described herein are methods of treating fibrosis specific monoclonal antibody and it showed that VDR is that are based on the unexpected discovery that a specialized present in day 3 hepatic stellate cells.
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