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WO 2013/168162 A9 14 November 2013 (14.11.2013) P O P C T

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WO 2013/168162 A9 14 November 2013 (14.11.2013) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) CORRECTED VERSION (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2013/168162 A9 14 November 2013 (14.11.2013) P O P C T (51) International Patent Classification: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, C12Q 1/68 (2006.01) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (21) International Application Number: NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, PCT/IL2013/050398 RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, (22) International Filing Date: TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, May 2013 (09.05.2013) ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 61/644,840 ' May 2012 (09.05.2012) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, LV, (71) Applicant: YISSUM RESEARCH DEVELOPMENT MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, COMPANY OF THE HEBREW UNIVERSITY OF TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, JERUSALEM LTD. [IL/IL]; Hi-Tech Park, Edmond ML, MR, NE, SN, TD, TG). Safra Campus, Givat Ram, 9 1390 Jerusalem (IL). Declarations under Rule 4.17 : (72) Inventors: SOREQ, Hermona; 14 HaMaayan Street, Ein — of inventorship (Rule 4.17(iv)) Kerem, 95903 Jerusalem (IL). SKLAN, Ella; 22 Hasharon Street, 43352 Raanana (IL). SHENHAR-TSARFATY, Published: Shani; Kibbutz Gesher, 15 157 Jordan Valley (IL). HAN- — with international search report (Art. 21(3)) IN, Geula; 6 Karpas Street, Gilo, 93898 Jerusalem (IL). — with amended claims (Art. 19(1)) (74) Agent: REINHOLD COHN AND PARTNERS; P.o.b. 13239, 6 113 1 Tel Aviv (IL). — with sequence listing part of description (Rule 5.2(a)) (81) Designated States (unless otherwise indicated, for every (48) Date of publication of this corrected version: kind of national protection available): AE, AG, AL, AM, 3 April 2014 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (15) Information about Correction: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, see Notice of 3 April 2014 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, < 00 (54) Title: CLUSTERED SINGLE NUCLEOTIDE POLYMORPHISMS IN THE HUMAN ACETYLCHOLINESTERASE GENE o AND USES THEREOF IN DIAGNOSIS AND THERAPY (57) Abstract: The present invention relates to diagnostic and prognostic methods and kits for determining genetic predisposition for at least one AChE-associated disorder, as well for diagnosing, prognosing and monitoring said disorders. The methods of the in vention are based on detection of specific SNPs that modulate the interaction of different mi RNAs to AChE 3'-UTR. CLUSTERED SINGLE NUCLEOTIDE POLYMORPHISMS IN THE HUMAN ACETYLCHOLINESTERASE GENE AND USES THEREOF IN DIAGNOSIS AND THERAPY TECHNOLOGICAL FIELD The invention relates to diagnostic methods for determining genetic predisposition for disorders associated with acetylcholinesterase (AChE) signaling. More particularly, the invention provides methods and kits for detecting single nucleotide polymorphisms (SNPs) in the 3'-UTR of the AChE gene that modulate microRNA regulation of the AChE signaling. PRIOR ART References considered to be relevant as background to the presently disclosed subject matter are listed below: [I] Shapira, M. el al. Hum Mol Genet. 9:1273-81 (2000); [2] Soreq, H. and Seidman S. Nat Rev Neurosci. 9:670 (2001); [3] Filipowicz, W. et al. Nature reviews. Genetics 9:102-1 14 (2008); [4] Battel, D. P. Cell 136:215-233 (2009); [5] Lau, P. & de Strooper, B. Seminars in cell & developmental biology 21:768-773 (2010); [6] Abelson, J. F. et al. Science 310:317-320 (2005); [7] Martin, M. M. et al. The Journal of biological chemistry 282:24262-24269 (2007); [8] Sklan, E. H. et al. PNAS 101:5512-5517 (2004); [9] Landegren, U. et al, Genome Research 769(8):769-776 (1998); [10] Shi, M. M. Clinical Chemistry 47(2):164-172 (2001); [II] Albano F. et al. Journal of Hematology & Oncology 5:48 (2012); [12] Boissonneault, V. et al. JBC 284(4):1971-1981 (2009); [13] Robson, J. E. et al. RNA 18:135-144 (2012);] [14] Elmen, J. et al. Nature 452:896-899 (2008); [15] Xiaojuan, C. et al. Int. J. Mol. Sci. 14:7089-7108 (2013); [16] Ellman, G. L., et al., Biochem. Pharmacol. 7:88-95 (1961); [17] Pohanka, M. et al. Int. J. Mol. Sci. 12:2631-2640 (2011); [18] Birman, S. Biochem. J. 225:825-828 (1985); [19] Ofek, K. et al. J Mol Med (Berl) 85:1239-1251 (2007); [20] Hasin, Y. et al. Human mutation 24:408-416 (2004); [21] Hanin, G. & Soreq, H. Frontiers in molecular neuroscience 4:28 (2011); [22] Benmoyal-Segal, L. Faseb J 19:452-454 (2005); [23] Browne, R. O. et al. Faseb J 20:1733-1735 (2006); [24] Loewenstein-Lichtenstein, Y. et al. Nat Med 1:1082-1085 (1995); [25] Neville, L. F. et al. J Neurosci Res 27:452-460 (1990); [26] Podoly, E. et al. J Biol Chem 284:17170-17179 (2009); [27] Velan, B. et al. Cellular and molecular neurobiology 11:143-156 (1991); [28] Homola, J. Chemical reviews 108:462-493 (2008); [29] Jeyapalan, Z. et al. Nucleic acids research 39:3026-304 1 (2011); [30] Kang, J. G .et al. The Journal of pathology 225:378-389 (2011); [31] Papadopoulos, T. et al. The EMBO journal 26:3888-3899 (2007); [32] Vallieres, L. et al. The Journal of neuroscience : the official journal of the Society for Neuroscience 22:486-492 (2002); [33] Berson, A. et al. EMBO molecular medicine 4:730-742 (2012); [34] Prody et al. PNAS 84:3555-3559 (1987); [35] Soreq et al. PNAS 24:9688-92 (1990); [36] Kaufer, D. et al. Nature 393:373-377 (1998); [37] Pavlov, V. A. et al. Brain, behavior, and immunity 23:41-45 (2009); [38] Tyagarajan, S. K. et al. Journal of cell science 124(2):786-796 (201 1); [39] Guyenet, P. G. Nature reviews. Neuroscience 7:335-346 (2006); [40] Lettre, G. et al. PLoS genetics 7 el001300 (201 1); [41] Shaked, et al. Immunity 31:854-855 (2009). Acknowledgement of the above references herein is not to be inferred as meaning that these are in any way relevant to the patentability of the presently disclosed subject matter. BACKGROUND OF THE INVENTION Stress is known to activate numerous physiological systems in the body and hormones appear to play a pivotal role in translating the stress response in the brain into long-term functional changes in peripheral tissues and organs. Prolonged stress may be particularly detrimental. For example, early childhood self-reported anxiety and depression predict post-traumatic stress disorder (PTSD) following stress. Nevertheless, to date there are no objective prognostic tools available for large scale screening of trauma-exposed individuals to identify those with inherited susceptibility and allow selection for treatment. Such screening is especially valuable in light of studies suggesting the importance of early treatment; thus, Trauma-Focused early intervention based on cognitive-behavioral treatment was reported to be effective for individuals with traumatic stress symptoms. These results point to the importance of early screening and diagnosis of individuals in high risk for trauma-related psychopathologies. Cholinergic signaling in general and the ACh hydrolyzing enzyme Acetylcholinesterase (AChE) specifically, is simultaneously involved in central cognitive processes such as learning, memory and stress responses and in activating the parasympathetic system. Animal studies and some human data show that AChE, an essential controller of ACh levels, is subject to significant alterations following stress. The AChE extended promoter contains a functional glucocorticoid response element, leading to over-expression under stress. Additionally, alternative splicing replaces the synaptic AChE variant (AChE-S) with a normally rare soluble monomer form- "read-through" AChE (AChE-R). AChE-R may rapidly counteract and attenuate the effects of ACh hyper-secretion [1, 2], providing long-term protection from progressive neural injury. Importantly, several Middle-East abundant polymorphisms in the AChE and the homologous butyrylcholinesteras (BChE) gene could affect the ability of individuals to cope with cholinergic challenges. The known polymorphisms and biochemical variability of AChE further affect inherited trait and state anxiety. Additionally, as is reported herein, polymorphisms in the non- coding regions of these genes may affect the capacity of microRNAs (miRs) to regulate cholinesterase levels. MiRs are short non-coding RNAs, 20-25 nucleotides long, that can simultaneously regulate multiple gene functions in a single biological pathway [3] by post-transcriptionally suppressing translation or inducing degradation of their mRNA targets [4, 5]. However, the biological impact of maintaining the balance among multiple miR-target interactions or how impairments in one interaction would affect others has not been well studied. At the genomic level, SNP interference with miR functions was shown to affect the expression of these miRs' targets, modify higher brain functions and induce a risk of chronic disease. Examples include a 3'-UTR SNP in the brain-expressed human Slit and Trk-like 1 (SLITRK1) gene which strengthens an existing miR- 189 target site and is involved in Tourette's syndrome [6], and a 1166A/C SNP in the angiotensin receptor 1 (AGTR1) gene which abrogates its miR- 155-mediated regulation, resulting in elevation of the AGTR1 protein which is implicated in hypertension and cardiovascular disease [7].
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