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(12) Patent Application Publication (10) Pub. No.: US 2014/0088056A1 Ye Et Al US 20140O88056A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0088056A1 Ye et al. (43) Pub. Date: Mar. 27, 2014 (54) CARDIAC GLYCOSIDES ARE POTENT Publication Classification INHIBITORS OF INTERFERON-BETA GENE EXPRESSION (51) Int. Cl. A613 L/585 (2006.01) A 6LX3/59 (2006.01) (75) Inventors: Junqiang Ye, Fort Lee, NJ (US); A613 L/7 (2006.01) Shuibing Chen, Pelham, NY (US); Tom A 6LX3 L/505 (2006.01) Maniatis, New York, NY (US) A613 L/407 (2006.01) A63L/36 (2006.01) (52) U.S. Cl. (73) Assignee: PRESIDENT AND FELLOWS OF CPC ............. A6 IK3I/585 (2013.01); A61 K3I/407 HARVARD COLLEGE, Cambridge, (2013.01); A61 K3I/136 (2013.01); A61 K MA (US) 3 1/17 (2013.01); A61K3I/505 (2013.01); A6 IK3I/519 (2013.01) (21) Appl. No.: 13/876,795 USPC ........... 514/175: 514/410; 514/656; 514/597; (22) PCT Filed: Sep. 28, 2011 514/256; 514/264.11: 435/375; 435/184 (57) ABSTRACT (86). PCT No.: The invention provides for a method of inhibiting interferon S371 (c)(1), beta gene expression and/or reducing the level of interferon (2), (4) Date: Nov. 25, 2013 beta in a cell by contacting the cell with a Na", Ca", or K" ion-channel modulator. The invention also provides for a method of treating a disease or disorder characterized by Related U.S. Application Data elevated interferon beta levels or elevated levels of interferon (60) Provisional application No. 61/387,407, filed on Sep. beta gene expression. Additionally, the invention provides a 28, 2010. method for treating pathogenic or non-pathogenic infections. Patent Application Publication Mar. 27, 2014 Sheet 1 of 30 US 2014/0088056A1 Se 5 5. FIG. IA N ,- Se r E r t e s 8F s -- e -- as -- PR) PR3 R FIG. IB Patent Application Publication Mar. 27, 2014 Sheet 2 of 30 US 2014/0088056A1 PPPRSA Pip NFRSF2A EP CRS FS F3 RASSF S25.25 CK Si SP I3 PE8 RC 835 E3322 F393 CPA R839 RBS CSR. 3. AR R8 EA3 R PPR SR56 CRE8 BRS S Cliff EY Siii. F8 C38 G5 BSS PK Fi S3 iGF SPSB CEBP R i-8 Patent Application Publication Mar. 27, 2014 Sheet 3 of 30 US 2014/0088056A1 E pa al F Cxc ES5 CC FI 8 RG AS PPPRA OGP1 NS P Cited PRB4 PR6 ES S. Sey-NP Se GAPDH FIG. ID CRO POYC POY it BFA - . - - o -- FIG, IE Patent Application Publication Mar. 27, 2014 Sheet 4 of 30 US 2014/0088056A1 5 t E s i S s se ce a. NS & % Šs. % Patent Application Publication Mar. 27, 2014 Sheet 5 of 30 US 2014/0088056A1 Se FOR 15 RS CANE) Eji - "...". BFN REAE) . w FIG. 2E Bis BFA - - - -- NP) BON-SA BFN - Patent Application Publication Mar. 27, 2014 Sheet 6 of 30 US 2014/0088056A1 Ridds PE isRNA 3.5- as 3 S 2.5 2 s: 1.3 S.S ?h, re dsRNA + - - - - - - -- NaCl) . 38 OB 2.0 . RG-APaseoKCM. 30 00 200 Patent Application Publication Mar. 27, 2014 Sheet 7 of 30 US 2014/0088056A1 s 3.is Lu- isES 1. ; 2. 2 : F- - - - S 8 - -- Na+- BFA FIG. 3C Patent Application Publication Mar. 27, 2014 Sheet 8 of 30 US 2014/0088056A1 APa O 18. 29 i SSSF.C.is 8,rt, EEERNISific, Si WW iSE & I.S. f v. APa3 s 8 S 3 SE S.S.S.S.C.S.&S* , , , 's i.fi'8' xi. ESS): Y ESGISN.S fish, S. S. .. .x . if. R alala FIG. 4A N Se , 8 8 2 -- " - - - BUFALN - - - - - - - - - - - it SCOR Bia a SP33 FIG. 4B Patent Application Publication Mar. 27, 2014 Sheet 9 of 30 US 2014/0088056A1 N Se 8 f BUFALN - " - f. - - - BiPai Ripa 38 FIG. 4C N "Se Patent Application Publication Mar. 27, 2014 Sheet 10 of 30 US 2014/0088056A1 Pa ACN FIG. 5A 3. AN Fi 83 . 8,883 Se Act Se did CNR AP3 C, FIG. 5B Patent Application Publication Mar. 27, 2014 Sheet 11 of 30 US 2014/0088056A1 88 ACXCO 0.07 a 0.86 3 (.85 E 8.04 0.3 is 0.02 0.01 8 Se Aid T S Atti CR APa (NCK); FIG. 5C sh SCRABE AP NCER - Se C did - Se Eid FIG. 5D Patent Application Publication Mar. 27, 2014 Sheet 12 of 30 US 2014/0088056A1 8.84. OSE FN 8.835 a .830 (.625 E 0.020 if (5 0.018 9,005 ce ) Set i di Se iC At CONR) A Pa KNOCK FIG. 5E 3. SECC 2.5 2 2. E 1.5 10 is 8.5 to 8,8- F-fil Se : ; Se is tid COTR A Pa KNCK FIG. 5F Patent Application Publication Mar. 27, 2014 Sheet 13 of 30 US 2014/0088056A1 RSE RF til sts 8. 3. 3 8 E 8,006 Ea.004 E. is 8,902 ce 888 SetSe it dAid Sey C Ad CR Pai (NCK); FIG. 5G SCRAB, SCRABE-Sey &SCRAS-C SSCRABE-At SAP: 8Pai Se SAPai 88 Pai-it SRNA SCRARBE AIPlai SCRAABE APa SCRAYBE AFPla Stat rex RG FIG. 5H Patent Application Publication Mar. 27, 2014 Sheet 14 of 30 US 2014/0088056A1 e t N : (O9(5)IAI C19º?I,HI ######8- {{9(9.I.H. text ran we be in a w tes S8338 Patent Application Publication Mar. 27, 2014 Sheet 15 of 30 US 2014/0088056A1 B Set - - r FIG, 7B Patent Application Publication Mar. 27, 2014 Sheet 16 of 30 US 2014/0088056A1 Se - - - -- BFN - - - -- R3 ER RONGREER BFN Se : Ad - Se is did FN GAP FIG. 7D i Patent Application Publication Mar. 27, 2014 Sheet 17 of 30 US 2014/0088056A1 8 Se is .8 S , CNR 8 8 FIG. 8A 3 IN IS 2.5 C 2 5 E 8,3 i ri rii - CR ti O BF FIG. 8B Patent Application Publication Mar. 27, 2014 Sheet 18 of 30 US 2014/0088056A1 NCR AXE NOPINE PENA Se - - a - bh - FN C RG Sey NP GAPDH FIG. 9 Se C did BUFALN w v. FIG 10A Patent Application Publication Mar. 27, 2014 Sheet 19 of 30 US 2014/0088056A1 SCRAMBLE shRNA Pai siRNA F. FIG. 10B NNER Sey C dard BFA - -- al -- Wax -- sh -- Patent Application Publication Mar. 27, 2014 Sheet 20 of 30 US 2014/0088056A1 293 S3 - BFAN Fa 3 S 5 30 S Ba pKBa p-S276 p53 p-S468 p$5 p$536 pg5 staf bACTIN FIG. I2B Patent Application Publication Mar. 27, 2014 Sheet 21 of 30 US 2014/0088056A1 SSy se s Se:E YS san see N s Sa & > s s: Sis wnsS ar Q geS is Ns - is war era is a ti e if ge Y re s' s 8Se. i i. s -9 - ON s assar Patent Application Publication Mar. 27, 2014 Sheet 22 of 30 US 2014/0088056A1 FULL LENGTH (CEAVED ARP EAE PRP EAE) CSPSE3 FIG. 14A PARP shRNA Pa SR Se Ai - Se it FIG. 14B Patent Application Publication Mar. 27, 2014 Sheet 23 of 30 US 2014/0088056A1 BFA Exc RG Stati SG AP FIG. 15A CNR) PS BN FIG. 15B EGF BFA - - - x p-P42/44 P42s. FIG. 15C Patent Application Publication Mar. 27, 2014 Sheet 24 of 30 US 2014/0088056A1 i8 358 38 5 2688. 388 3 38 - - UNTREATED int. Only 10Bay it. Of Bt FIG. 16A s UNTREATED inly Only 100nM M 10M BFA FIG. 16B Patent Application Publication Mar. 27, 2014 Sheet 25 of 30 US 2014/0088056A1 F E"ENG PARP EAE PARP EE ASPASE3 FIG. 16D Patent Application Publication Mar. 27, 2014 Sheet 26 of 30 US 2014/0088056A1 YNSp 8 NGSp 8 3. s as a. Seea an i se c c c is as E s s w- re al s . e 'asad E . re E e 8 is QSs r N E s s -: QSN N (ONSN Patent Application Publication Mar. 27, 2014 Sheet 27 of 30 US 2014/0088056A1 8I’0IJI Patent Application Publication Mar. 27, 2014 Sheet 28 of 30 US 2014/0088056A1 CRO. Se BF ER RF3 ONER AP 283, shRNA FIG. 19A P BN-tisNA BFA -- - - 8 FIG. 19C Patent Application Publication Mar. 27, 2014 Sheet 29 of 30 US 2014/0088056A1 SRNA SCRA 8.E. t NCER . Sey did Setti Aid FIG. 19D CNR FA 28 3 is i 8 3 88 24 : KBa FIG. I9E Patent Application Publication Mar. 27, 2014 Sheet 30 of 30 US 2014/0088056A1 SAFE XC s 151 as in g|MOUSE EFFECES OF BFAN N A Pa KNOCK-NEESRYA FIG. 20A IBF "S) . 23 28 3. l 68 $ii HOURS POSLPS INECTION (80 mg/kg) FIG. 20B US 2014/0088056A1 Mar. 27, 2014 CARDAC GLYCOSDES ARE POTENT Rosen, A. Type I interferons: crucial participants in disease INHIBITORS OF INTERFERON-BETA GENE amplification in autoimmunity. Nat Rev Rheumatol 6, 40-9. EXPRESSION Overproduction of interferon has been recognized as the major cause of systemic lupus erythematosus (SLE) RELATED APPLICATIONS (Banchereau, J. & Pascual, V. Type I interferon in systemic 0001. This application claims benefit under 35 U.S.C. lupus erythematosus and other autoimmune diseases. Immu S119(e) of the U.S. Provisional Application No. 61/387,407, nity 25, 383-92 (2006)). In addition, strong innate immune filed Sep. 28, 2010, content of which is incorporated herein by responses (including IFN production) have been shown to reference in its entirety. contribute to AIDS virus infection (Mandl, J. N. et al.
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