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(12) United States Patent (10) Patent No.: US 9,163,078 B2 Rao Et Al

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(12) United States Patent (10) Patent No.: US 9,163,078 B2 Rao Et Al US009 163078B2 (12) United States Patent (10) Patent No.: US 9,163,078 B2 Rao et al. (45) Date of Patent: *Oct. 20, 2015 (54) REGULATORS OF NFAT 2009.0143308 A1 6, 2009 Monk et al. 2009,0186422 A1 7/2009 Hogan et al. (75) Inventors: Anjana Rao, Cambridge, MA (US); 2010.0081129 A1 4/2010 Belouchi et al. Stefan Feske, New York, NY (US); Patrick Hogan, Cambridge, MA (US); FOREIGN PATENT DOCUMENTS Yousang Gwack, Los Angeles, CA (US) CN 1329064 1, 2002 EP O976823. A 2, 2000 (73) Assignee: Children's Medical Center EP 1074617 2, 2001 Corporation, Boston, MA (US) EP 1293569 3, 2003 WO 02A30976 A1 4, 2002 (*) Notice: Subject to any disclaimer, the term of this WO O2/O70539 9, 2002 patent is extended or adjusted under 35 WO O3/048.305 6, 2003 U.S.C. 154(b) by 0 days. WO O3/052049 6, 2003 WO WO2005/O16962 A2 * 2, 2005 This patent is Subject to a terminal dis- WO 2005/O19258 3, 2005 claimer. WO 2007/081804 A2 7, 2007 (21) Appl. No.: 13/161,307 OTHER PUBLICATIONS (22) Filed: Jun. 15, 2011 Skolnicket al., 2000, Trends in Biotech, vol. 18, p. 34-39.* Tomasinsig et al., 2005, Current Protein and Peptide Science, vol. 6, (65) Prior Publication Data p. 23-34.* US 2011 FO269174 A1 Nov. 3, 2011 Smallwood et al., 2002, Virology, vol. 304, p. 135-145.* • - s Chattopadhyay et al., 2004. Virus Research, vol. 99, p. 139-145.* Abbas et al., 2005, computer printout pp. 2-6.* Related U.S. Application Data Strausberg et al., 2004, GenEmbl Accession No. BC069270, com AV puter printout, pp. 13-17.* (63) Continuation of application No. 12/160.030, filed as Roos et al., 2007, US 2007003 1814 A1, effective filing date Mar. 4, application No. PCT/US2007/000280 on Jan.5, 2007. 2003.* (60) Provisional application No. 6O7756 934 filed on Jan. Zhang et al., U.S. Appl. No. 1 1/582,861, US 20070099251, effective 5, 2006 s- - is filing date Oct. 17, 2005, see computer printout, pp. 8-10.* s Harkinet al., U.S. Appl. No. 1 1/266,748, US 20060134663, effective (51) Int. Cl. filing date Jul. 18, 2005, computer printout, pp. 6-9.* CI2O I/00 (2006.01) (Continued) A6 IK 4.8/00 (2006.01) CI2N 15/63 (2006.01) C7H 2L/04 (2006.01) Primary Examiner — Shin Lin Chen OW' 3:08: (74) Attorney, Agent, or Firm — Nixon Peabody LLP CI2N 5/16 (2006.01) CI2N 15/90 (2006.01) (57) ABSTRACT (52) U.S. Cl. CPC ............ C07K 16/18 (2013.01); G0IN33/5041 Disclosed are methods of identifying an agent that modulates (2013.01); C07H21/04 (2013.01); C12N 5/16 an NFAT regulator protein. One such method comprises con (2013.01); C12N 15/63 (2013.01); C12N tacting at least one test agent with a recombinant cell com I 5.90. (2013.01); C12O 1/00 (2013.01) prising at least one NFAT regulator protein or fragment or (58) Field of Classification Search derivative thereof, assessing the effect of the test agent on an CPC ........ C12N 5/16: C12N 15/63; C12N 15/907; activity, interaction, expression, or binding to the NFAT regu f C2Q 1f9. SOH 1/04 lator protein or fragment orderivative thereof, and identifying S. licati - - - - - is . 4. i. 424 R 536/23.5 the test agent that has an effect on an activity, interaction, ee application file for complete search history. expression, or binding to the NFAT regulator protein or frag (56) References Cited ment orderivative thereof, whereby the identified testagent is characterized as an agent that modulates an NFAT regulator U.S. PATENT DOCUMENTS protein. Methods of identifying an agent that modulates intra cellular calcium, methods to screen for an agent that modu 6,875,581 B1 4/2005 Voelkel 2001 OO18196 A1 8, 2001 Mendoza et al. lates NFAT regulator function, methods to diagnose unex 2004/0219521 A1 1 1/2004 Tang et al. plained immunodeficiency in a Subject, and methods for 2005/0107588 A1 5/2005 Duggan et al. identifying an agent for treating or preventing a disease or 2005/0255487 A1 11, 2005 Khvorova et al. 2006/0286605 A1 12/2006 Liou et al. disorder associated with a NFAT regulator protein or calcium 2007/0031814 A1 2/2007 Roos et al. signaling are also disclosed. 2008, OO39392 A1 2/2008 Cahalan 2008/0096,227 A1 4/2008 Penner 2008/0293,092 A1 11/2008 Stauderman et al. 27 Claims, 33 Drawing Sheets US 9,163,078 B2 Page 2 (56) References Cited Kim, E. and Sheng, M., “PDZDomain Proteins of Synapses.” Nature Reviews Neuroscience 5:771-781, 2004. OTHER PUBLICATIONS Kotturi, M. F. et al., “Identification and Functional Characterization Strausberg et al., 2004, GenEmbl Accession No. BC075831, direct of Voltage-dependent Calcium Channels in T Lymphocytes.” J Biol submission on Jul. 6, 2004, ORAI1. Strauysberg1.* Chem 278(47):46949-46960, 2003. Krogh, A. et al., “Predicting Transmembrane Protein Topology with Strausberg et al., 2004, GenEmbl Accession No. BC069270, direct a Hidden Markov Model: Application to Complete Genomes.” J Mol submission on Apr. 26, 2004, ORAI2, Strausberg2.* Biol 305:567-580, 2001. Strausberg et al., 2001, GenEmbl Accession No. BC015555, direct Le Deist, F. et al., “A primary T-cell immunodeficiency associated submission on Oct. 1, 2001, ORAI3, Strausberg3.* with defective transmembrane calcium influx.' Blood 85: 1053-1062, Abecasis, G. R. et al., “Merlin-rapid analysis of dense genetic maps 1995. using sparse gene flow trees.” Nature Genetics 30: 97-101, 2002. Lepple-Wienhues, A. and Cahalan. M. D., "Conductance and Perme Altshuler, D. et al., “Ahaplotype map of the human genome.” Nature ation of Monovalent Cations through Depletion-Activated Ca2+ 437(7063): 1299-1320, 2005. Channels (Icrac) in Jurkat T Cells.” Biophysical Journal 71:787-794, Aramburu, J. et al., "Affinity-Driven Peptide Selection of an NFAT 1996. Inhibitor More Selective Than Cyclosporin A,” Science 285:2129 Lewis, R. S., "Calcium Signaling Mechanisms in T Lymphocytes.” 2133, 1999. Annu Rev Immunol 19:497-521, 2001. Badou, A. et al., “Requirement of Voltage-Gated Calcium Channel B4 Leykin, I. et al., “Comparative linkage analysis and visualization of Subunit for T Lymphocyte Functions.” Science 307: 117-121, 2005. high-density oligonucleotide SNP array data.” BMC Genetics 6(7): 1 Beals, C. R. et al., “Nuclear Export of NF-ATc Enhanced by Glyco 16, 2005. gen Synthase Kinase-3.” Science 275:1930-1933, 1997. Liou, J. et al., “STIM Is a Ca2+ Sensor Essential for Ca2+-Store Clipstone, N. A. et al., “Molecular Analysis of the Interaction of Depletion-Triggered Ca2+ Influx.” Current Biology 15:1235-1241, Calcineurin with Drug-Immunophilin Complexes.” J Biol Chem 2005. 269(42): 26431-26437, 1994. Liu, J., “FK506 and cyclosporin, molecular probes for studying Courtois, G. et al., “A hypermorphic 1-kappa-B-beta mutation is intracellular signal transduction.” Immunology Today 14(6):290-295, 1993. associated with autosomal dominant anhidrotic ectodermal dysplasia Macian, F. “NFAT Proteins: Key Regulators of T-Cell Development and T cell immunodeficiency.” JClin Invest 112:1108-1115, 2003. and Function.” Nature 5:472-484, 2005. Crabtree, G. R. and Olson, E.N., "NFATSignaling: Choreographing Macian, F. “Partners in transcription: NFAT and AP-1.” Oncogene the Social Lives of Cells' Cell 9:S67-S79, 2002. 20:2476-2489, 2001. Cui, J. et al., “CaT1 Contributes to the Stores-operated Calcium Mori, Y. et al., “Transient Receptor Potential 1 Regulates Capacita Current in Jurkat T-lymphocytes' J Biol Chem 277 (49)47175 tive Ca2+Entry and Ca2+ Release from Endoplasmic Reticulum in B 47183, 2002. Lymphocytes.” J Exp Med 195(6)673-681, 2002. Döffinger, R. "X-linked anhidrotic ectodermal dysplasia with Myers, E. W. et al., “A Whole-Genome Assembly of Drosophila.” immunodeficiency is caused by impaired NF-kappa-B signaling.” Science 287:2196-2204, 2000. Nature Genetics 27:277-285, 2001. Okamura, H. et al., “Concerted Dephosphorylation of the Transcrip Feske, S. et al., “The Duration of Nuclear Residence of NFAT Deter tion Factor NFAT1 Induces a Conformational Switch that Regulates mines the Pattern of Cytokine Expression in Human SCIDT Cells.” Transcriptional Activity.” Molecular Cell 6:539-550, 2000. J Immunol 165:297-305, 2000. Okamura, H. et al., “A Conserved Docking Motif for CK1 Binding Feske, S. et al., “Gene regulation mediated by calcium signals in T Controls the Nuclear Localization of NFAT1...' Molecular and Cellu lymphocytes.” Nature Immunology 2(4):316-324, 2001. lar Biology 24(10):4184-4195, 2004. Feske, S. et al., “A mutation in Orail causes immune deficiency by Parekh, A. B. and Putney, Jr., J. W. “Store-Operated Calcium Chan abrogating CRAC channel function.” Nature 441: 179-185, 2006. nels” Physiol Rev 85:757-810, 2005. Feske, S. et al., “A severe defect in CRAC Ca2+ channel activation Parekh, A. B. and Penner, R., “Store Depletion and Calcium Influx.” and altered K+ channel gating in T cells from immunodeficient Physiological Reviews 77(4):901-930, 1997. patients.” JEM 202(5):651-662, 2005. Partiseti, M. et al., “The Calcium Current Activated by T Cell Recep Feske, S. et al., "Ca2+/calcineurin signalling in cells of the immune tor and Store Depletion in Human Lymphocytes is Absent in a Pri system.” Biochemical and Biophysical Research Communications mary Immunodeficiency.” JBiol Chem 269(51):32327-32335, 1994. 3 11:1117-1132, 2003. Philipp, S. et al., “TRPC3 Mediates T-cell Receptor-dependent Cal Gabriel, S. B. et al., “The Structure of Haptotype Blocks in the cium Entry in Human T-lymphocytes.” J Biol Chem 278(29):26629 Human Genome.” Science 296:2225-2229, 2002. 26638, 2003.
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