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(12) Patent Application Publication (10) Pub. No.: US 2010/0222283 A1 Susztak Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0222283 A1 Susztak Et Al US 2010O222283A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0222283 A1 Susztak et al. (43) Pub. Date: Sep. 2, 2010 (54) USE OF GAMMA SECRETASE INHIBITORS (86). PCT No.: PCT/USO8/10362 AND NOTCH PATHWAY INHIBITORS FOR TREATMENT AND PREVENTION OF RENAL S371 (c)(1), DESEASE (2), (4) Date: Apr. 30, 2010 Related U.S. Application Data (76) Inventors: Katalin Susztak, Cresskill, NJ (60) Provisional application No. 60/993,865, filed on Sep. (US); Bernhard Bielesz, Rye, NY 14, 2007. Bronx,(US); Thiruvur NY (US) G. Niranjan, PublicationO O Classification (51) Int. Cl. A638/05 (2006.01) Correspondence Address: A6II 3/55 (2006.01) AMSTER, ROTHSTEIN & EBENSTEIN LLP A6II 3L/225 (2006.01) 90 PARKAVENUE A6IPI3/2 (2006.01) NEW YORK, NY 10016 (US) (52) U.S. Cl. ....... 514/19:514/217: 514/548: 514/212.04 (57) ABSTRACT (21) Appl. No.: 12/733,339 Methods are provided for treating and preventing renal dis ease in a Subject by administering a gamma Secretase inhibi (22) PCT Filed: Sep. 4, 2008 tor or a Notch pathway inhibitor to the subject. Os s :. s Patent Application Publication US 2010/0222283 A1 Figure 1A-1E Patent Application Publication Sep. 2, 2010 Sheet 2 of 12 US 2010/0222283 A1 T_LO dNC] SSDS-3 Figure 2A-2C Patent Application Publication Sep. 2, 2010 Sheet 3 of 12 US 2010/0222283 A1 W NC1 tA rTA CN 1000 g AICN1 t O E s d 0.1 O. s . s : Figure 3A-3F Patent Application Publication Sep. 2, 2010 Sheet 4 of 12 US 2010/0222283 A1 easins insister vers (podocin tTA mice) doxycyclire --- icni (tetO-NICD mice) 33 O5 5 Figure 4A-4D Patent Application Publication Sep. 2, 2010 Sheet 5 of 12 US 2010/0222283 A1 a b 1 40 Vector EIN E E EIN EN EN g 120 Tarn - - 0.75 0.75 15 3 5 10. 80 val1744N1 S 6. f 5 4. 3-actin Wector EN E E EI EIN EN Cleaved am - 15 0.75 5 3 PARP C s Cleaved S Casp3 i ed s 3: p53 SD a. 2 www.2^xxoxw8X-wxWaxww. a. a X a. As A. a. w Wector EIN E E EIN EN EN EN EIN Tam - - 3 0.75 15 3 3 3 Z-wad - is v - - 10 - d Z-LEHD - - - - - - - 10 35 OVEGF 30 2 35 TGFB 25 2 30 É 20 2, 25 S 2S 2O 5 2N 2 2S 15 10 N | 2N i: 5 NS 2S2N 10 Na2S 5 N: 2N O Ef E. vector EIN E E ENENEN Tarr p 1.5 O.75 1.5 3 Figure 5A-5E Patent Application Publication Sep. 2, 2010 Sheet 6 of 12 US 2010/0222283 A1 - Relative mRNA a 0.75 0.75t 1.5M 3u M Tam an Tan EGFP an EGFP EGFP EGFP CT CN1 EGFP CN1 TICN CN1 100 109 109 427 720 1413 1.88 180 1435 26.62 1704 181 112 0.79 152 106 125 0.78 0.58 169 063 Wector EN E E EIN EN EN c Tam - 0.75 0.75 15 3 Figure 6A-6C Patent Application Publication Sep. 2, 2010 Sheet 7 of 12 US 2010/0222283 A1 a SB PD Y GS -- -- s s -- a TGFB(min) - 5 30 60 120 240 5 30 60 120 240 60 60 60 :: : : b GSI - - TGFB(hr) - - - - - - - PF C GSI - 1 4 24 1 4 24 24 O 5 5 O O CTL TGFp TGFb TGFB CTL TGFB TGFB TGFB GSE XX PF GSXX GSX Figure 7A-7E Patent Application Publication Sep. 2, 2010 Sheet 8 of 12 US 2010/0222283 A1 3. -- -- + + + -- -- - 5 30 60 120 240 5 30 60 120 240 P Figure 8A-8B Patent Application Publication Sep. 2, 2010 Sheet 9 of 12 US 2010/0222283 A1 b CL Het DM OKO DM B CT Het-DN KO-DM Nephrin Podocin CTL Het DM CTL Het DM KODM 2O e e C. COO Het DM 3. 80 KO DM e 600 KO DM 400 TGFB VEGF Figure 9A-9E Patent Application Publication Sep. 2, 2010 Sheet 10 of 12 US 2010/0222283 A1 a Nephrin 18 Podocin S WEGF 14 12 0.8 OS O4 O.2 O 8:8 R p Rbplox/WT R pjioxifox b ce ce ce 5 350 3. 25 2O) SO 5 RbpwTwT Rbpjfloxwt Rbpjtioxiflox Rbpiloxiflox Ce Ce Cre Cre DM Mice n= Weight Glucose WT 5 34.94 1286 KO 5 32.65.4 17123 CTL Het DM 10 23.43.4 6000 Het Dr. KCM KO DM 10 24.31.5 576-28 23.4.56 Combined Cellularity Mesangial Expansion Figure 10A-10D Patent Application Publication Sep. 2, 2010 Sheet 11 of 12 US 2010/0222283 A1 CTL P Figure 11A-11F Patent Application Publication Sep. 2, 2010 Sheet 12 of 12 US 2010/0222283 A1 O..2 CTL PAN wai PAN B2AN Not No.2 O2 3. es Hess ey 40 3. s 3. 25 2. 15 s Figure 12A-12C US 2010/0222283 A1 Sep. 2, 2010 USE OF GAMMA SECRETASE INHIBITORS 0008. The Notch signaling pathway comprises a family of AND NOTCH PATHWAY INHIBITORS FOR transmembrane receptors, their ligands, negative and positive TREATMENT AND PREVENTION OF RENAL modifiers, and transcription factors'''. To date, 4 mamma DESEASE lian receptors (Notch1 through Notch4) and at least 5 ligands (Delta 1, 3, and 4 and Jagged 1, 2) have been identified. CROSS-REFERENCE TO RELATED Binding of the ligand renders the Notch receptor susceptible APPLICATION to metalloprotease- and Y-secretase-mediated proteolytic 0001. This application claims the benefit of U.S. Provi cleavage, which in turn results in the release of the Notch sional Patent Application No. 60/993,865, filed on Sep. 14, intracellular domain (ICN) from the plasma membrane and its subsequent translocation into the nucleus. Once there, ICN 2007, the content of which is hereby incorporated by refer associates with DNA-binding protein recombination signal ence into the Subject application. binding protein JK/CBF1/Su (H)/Lag-1 (Rbp) and master STATEMENT OF GOVERNMENT SUPPORT mind-like (MAML) protein, which recruit additional factors with histone acetylase activity, such as p300 and p300/ 0002. The invention disclosed herein was made with U.S. CREB-binding protein-associated factor. These proteins Government support from National Institute of Health Grant form a heteromeric complex that mediate transcription of 1R01-DK076077 (NIDDK), U.S. Department of Health and target genes, including basic helix-loop-helix transcription Human Services. Accordingly, the U.S. Government has cer factors of the hairy and enhancer of split (Hes) family and the tain rights in this invention. Hes-related repressor protein (Hey) family'. 0009. The Notch pathway plays a crucial role in podocyte FIELD OF THE INVENTION development. Genetic deletion of presenilin, Notch2 or treat 0003. The present invention relates to treatment and pre ment of developing kidney explants with a Y-secretase inhibi vention of kidney disease using Notch pathway inhibitors tor (GSI) leads to metanephric mesenchyme that produces Such as, for example, gamma secretase inhibitors. nephrons without glomeruli, proximal tubules, and loops of Henle but contain distal tubules that are correctly fused to the BACKGROUND OF THE INVENTION collecting duct'''. This may be due to the fact that cells in 0004 Various publications are referred to throughout this the absence of active Notch2 fail to proliferate and fail to application. Citations for these references may be found at the downregulate Pax2''. Patients with Alagile syndrome, who end of the specification immediately preceding the claims. lack one copy of Notch2 present with similar renal develop The disclosures of these publications are hereby incorporated mental abnormalities as well'7. Very little is known about by reference in their entireties into the subject application to Notch signaling in the kidney beyond renal development. more fully describe the art to which the subject application While during development the kidney has one of the highest pertains. levels of Notch activity, very little Notch activity can be 0005 Kidney diseases are estimated to affect up to 10 detected in the mature mouse kidney'. million people worldwide. Diabetic nephropathy (DNP) and 0010 Renal disease is currently treated using angiotensin focal segmental glomerulosclerosis (FSGS) are the two major inhibitors (ACE inhibitors) and angiotensin receptor block causes of end-stage renal disease (ESRD), accounting for ers, although these treatments typically only slow progression more than half of the ESRD cases in the US. Diagnoses of of the disease. Accordingly, there is a need for new therapy to FSGS and DNP are based on the clinical findings of pro prevent and treat renal disease. teinuria and histological scarring of the renal glomerulus, the major filtering apparatus of the kidney. SUMMARY OF THE INVENTION 0006 Podocytes, the visceral epithelial cells of the glom 0011. The present invention provides methods of treating erulus, have recently taken center stage in research on the and preventing renal disease in a Subject, where the methods pathogenesis of FSGS. Genetic studies in both human and involve administering to the subject a Notch pathway inhibi mouse reveal that the development of FSGS is initiated by tor, such as a gamma secretase inhibitor, in an amount effec podocyte dysfunction. Inherited mutations is likely respon tive to treat or prevent renal disease in the subject. sible for this disease in only a minor fraction of patients. 0007 Diabetic nephropathy is characterized by mesangial BRIEF DESCRIPTION OF THE FIGURES expansion and thickening of the glomerular basement mem brane leading to mesangial expansion and focal and nodular 0012 FIG.
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