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(12) Patent Application Publication (10) Pub. No.: US 2006/0160867 A1 Freedman (43) Pub

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(12) Patent Application Publication (10) Pub. No.: US 2006/0160867 A1 Freedman (43) Pub US 2006O160867A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0160867 A1 Freedman (43) Pub. Date: Jul. 20, 2006 (54) METHODS FOR MODULATING PPAR (60) Provisional application No. 60/466,672, filed on Apr. BOLOGICAL ACTIVITY FOR THE 30, 2003. TREATMENT OF DISEASES CAUSED BY MUTATIONS IN THE CFTR GENE Publication Classification (76) Inventor: Steven D. Freedman, Chestnut Hill, MA (US) (51) Int. Cl. A6II 3/426 (2006.01) Correspondence Address: A6II 3L/98 (2006.01) CLARK & ELBNG LLP (52) U.S. Cl. ............................................ 514/369; 514/567 101 FEDERAL STREET BOSTON, MA 02110 (US) (21) Appl. No.: 11/262,645 (57) ABSTRACT (22) Filed: Oct. 31, 2005 This invention features methods for treating diseases asso ciated with mutations in the CFTR gene by administering Related U.S. Application Data PPAR agonists, specifically PPARy, PPARC, and PPARö agonists, PPAR inducers, and/or antioxidants. Also dis (63) Continuation-in-part of application No. PCT/US04/ closed are screening methods for identifying therapeutically 13412, filed on Apr. 30, 2004. useful candidate compounds. Patent Application Publication Jul. 20, 2006 Sheet 1 of 19 US 2006/0160867 A1 sg O O O O O O CN O OO CO w CN 3 3 S. w w uoissedxe LM JO % Patent Application Publication Jul. 20, 2006 Sheet 2 of 19 US 2006/0160867 A1 2 O) C 2 E O 2 C O O ( ) O L) V cy) CN w O (c-OX) WNAS8 falo Patent Application Publication Jul. 20, 2006 Sheet 3 of 19 US 2006/0160867 A1 Figure 3. Patent Application Publication Jul. 20, 2006 Sheet 4 of 19 US 2006/0160867 A1 s O O s 2 t 5 H O e 2 - & 3 se S S & e O '... wild go uoqequenbouneuo-Isued O res > O s Z. rf CD . s T Z. Patent Application Publication Jul. 20, 2006 Sheet 5 of 19 US 2006/0160867 A1 igure 5: Patent Application Publication Jul. 20, 2006 Sheet 6 of 19 US 2006/0160867 A1 5 s O Cd C O Cd o O O r cN d od O w CN vr ve v na uossedXe LM JO % 5 s < uoisseudyce LWJO % Patent Application Publication Jul. 20, 2006 Sheet 7 of 19 US 2006/0160867 A1 Patent Application Publication Jul. 20, 2006 Sheet 8 of 19 US 2006/0160867 A1 0.08 O.O7 O.06 O.05 0.04 O.03 O.02 O.O1 O.OO Figure 8. Patent Application Publication Jul. 20, 2006 Sheet 9 of 19 US 2006/0160867 A1 0.01 0.009 0.008 0.007 0.006 0.005 0.004 0.003 0.002 0.001 O Figure 9. Patent Application Publication Jul. 20, 2006 Sheet 10 of 19 US 2006/0160867 A1 A - B WT+DSS WT+DHA CF CF+DSS CF+DHA Figure 10. Patent Application Publication Jul. 20, 2006 Sheet 11 of 19 US 2006/0160867 A1 Figure 11. Patent Application Publication Jul. 20, 2006 Sheet 12 of 19 US 2006/0160867 A1 Figure 12. Patent Application Publication Jul. 20, 2006 Sheet 13 of 19 US 2006/0160867 A1 Figure 13. Patent Application Publication Jul. 20, 2006 Sheet 14 of 19 US 2006/0160867 A1 Figure 14. Patent Application Publication Jul. 20, 2006 Sheet 15 of 19 US 2006/0160867 A1 NK-KB activity in macrophages O.35 & O3 O.25 O2 O.15 O1 O.05 WT CF WTHDHA CFDHA Figure 15. Patent Application Publication Jul. 20, 2006 Sheet 16 of 19 US 2006/0160867 A1 INEC, secretion L-6 secretion A. -O- CF e 9 -O- CF+DHA se 2 8 -a- WT 5 SS 6 S. 5 A. 2 32 1 O O O 1 10 100 1000 O 1 10 100 1000 LPS (ng/ml) LPS (ng/ml)lm Figure 16. Patent Application Publication Jul. 20, 2006 Sheet 17 of 19 US 2006/0160867 A1 LPS induced NFg secretion in peritoneal macrophages A. A. A t A k A x. 8 3. O & Figure 17. Patent Application Publication Jul. 20, 2006 Sheet 18 of 19 US 2006/0160867 A1 LPS induced L-6 secretion in peritoneal macrophages r rary t At A 8 e3 & Figure 18. Patent Application Publication Jul. 20, 2006 Sheet 19 of 19 US 2006/0160867 A1 LXR protein expression by western blot analysis in macrophages 50 la 30 a. Figure 19. US 2006/01 60867 A1 Jul. 20, 2006 METHODS FOR MODULATING PPAR SUMMARY OF THE INVENTION BOLOGICAL ACTIVITY FOR THE TREATMENT OF DISEASES CAUSED BY MUTATIONS IN THE 0007. The invention features a method for treating a CFTR GENE disease in a human patient that has a mutation in the CFTR gene by administering to the patient a therapeutically effec CROSS-REFERENCE TO RELATED tive amount of a peroxisome proliferator-activated receptor APPLICATIONS (PPAR) inducer, a PPAR agonist, an AP-1 inhibitor, a STAT inhibitor, an NFkB inhibitor, or an LXR agonist. PPARs 0001. This application is a Continuation-in-part applica generally include PPARC, PPARö, and PPARy. Diseases tion of and claims priority to International Application No. caused by mutations in a CFTR gene include, for example, PCT/US2004/013412, filed Apr. 30, 2004, which was pub cystic fibrosis, pancreatitis, chronic obstructive pulmonary lished in English under PCT Article 21(2), and which claims disease (COPD), asthma, chronic sinusitis, primary Scleros the benefit of U.S. provisional application No. 60/466,672, ing cholangitis, liver disease, bile duct injury, and congenital filed Apr. 30, 2003, both of which are incorporated herein by bilateral absence of the was deferens. The diseases that are reference in their entirety. treatable by the therapeutic methods of the invention include any disease caused by any of the 1,300 or more mutations in STATEMENT AS TO FEDERALLY SPONSORED the CFTR protein. See for example, J. Zielenski, Canadian RESEARCH CF registry database; Cutting et al., Nature 346:366-369, 0002 This invention was funded by grant R01 DK52765 1990; Dean et al., Cell 61:863-870, 1990; Kerem et al., from the National Institute of Health. The government may Science 245:1073-1080, 1989: Kerem et al., Proc. Natl. Acad. Sci. USA 87:8447-8451, 1990; and Welsh et al., have certain rights in the invention. “Cystic Fibrosis.” Metabolic and Molecular Basis of Inher ited Disease (8" Ed. 2001), pp. 5121-88. Particularly ame FIELD OF THE INVENTION nable to treatment are diseases caused by a deletion of the 0003. The present invention relates to the treatment of phenylalanine normally present at amino acid residue 508 of cystic fibrosis and other diseases associated with mutations the CFTR protein (AF508). The patients being treated in the CFTR gene. according to the methods of this invention may be heterozy gous or homozygous for a CFTR mutation. BACKGROUND OF THE INVENTION 0008 Useful PPAR inducers and agonists affect any 0004 Approximately one in 2000 Caucasians have cystic PPAR, but particularly PPARy, (e.g., PPARy1 and PPARy2), fibrosis (CF), a genetic disorder caused by inactivating PPARC, and PPARö. Examples include eicosapentaenoic mutations in the cystic fibrosis transmembrane conductance acid; any of the thiazolidinediones, but particularly piogli regulator (CFTR) gene. The CFTR protein, a member of the taZone (ACtosTM, Takeda Pharmaceuticals), rosiglitazone ABC transporter family, forms a chloride channel localized (AvandiaTM, GlaxoSmithKline), thioglitazone and analogs to the plasma membrane. The protein consists of five thereof; L-tyrosine derivatives such as fluoromethyloxycar domains: two membrane-spanning domains that form the bonyl; non-steroidal anti-inflammatory drugs such as chloride ion channel, two nucleotide-binding domains that indomethacin, ibuprofen, naprosyn, and fenoprofen; and hydrolyze ATP, and a regulatory domain. Expression of the anti-oxidants such as vitamin E. vitamin C, S-adenosyl CFTR gene is highest in cells that line passageways of the methionine, selenium, idebenone, cysteine, dithioerythritol, lungs, pancreas, colon, ileum, and genitourinary tract. dithionite, dithiothreitol, and pyrosulfate. Additional examples of PPARC agonists and inducers include DHA. 0005. In addition to CF, defects in the CFTR gene are WY14643, and any of the fibrates, particularly, fenofibrate, associated with diseases including, for example, pancreati beZafibrate, gemfibrozil, and analogs thereof. tis, chronic obstructive pulmonary disease (COPD), asthma, chronic sinusitis, primary Sclerosing cholangitis, and con 0009. In one example, the method includes the use of a genital bilateral absence of the vas deferens (CBAVD). PPARC. antagonist for the treatment of bile duct injury or 0006 The most common inactivating mutation of the cystic fibrosis liver disease associated with a mutation in a CFTR gene, detected in about 70% of CF patients, is a CFTR gene. deletion of the three base pairs encoding the phenylalanine 0010. The invention also features a method for treating a at amino acid residue 508 (AF508). The F508 residue is disease in a human patient that has a mutation in the CFTR located in a membrane spanning domain and its deletion gene by administering to the patient a therapeutically effec causes incorrect folding of the newly synthesized protein. As tive amount of a PPARC agonist and a therapeutically a result, misfolded protein is degraded in the endoplasmic effective amount of a PPARY agonist, including but not reticulum shortly after synthesis. Patients having a homozy limited to, the compounds described herein. gous AF508 deletion tend to have the most severe symptoms of cystic fibrosis, resulting from a loss of chloride ion 0011. The invention also features a method for treating a transport. The disturbance in the sodium and chloride ion disease in a human patient that has a mutation in the CFTR balance in the cells lining the respiratory tract results in a gene by administering to the patient a therapeutically effec thick, Sticky mucus layer that is not easily removed by the tive amount of a dual PPARC/PPARY agonist.
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