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WO 2016/069591 A2 6 May 2016 (06.05.2016) W P O P C T

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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/069591 A2 6 May 2016 (06.05.2016) W P O P C T (51) International Patent Classification: (74) Agents: KOWALSKI, Thomas, J. et al; Vedder Price C12N 15/10 (2006.01) C12N 15/90 (2006.01) P.C., 1633 Broadway, New York, NY 1001 9 (US). C12N 15/63 (2006.01) C12Q 1/68 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/US2015/057567 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (22) International Filing Date: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 27 October 2015 (27.10.201 5) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (25) Filing Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (26) Publication Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (30) Priority Data: SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 62/122,686 27 October 2014 (27. 10.2014) US TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicants: THE BROAD INSTITUTE INC. [US/US]; (84) Designated States (unless otherwise indicated, for every 415 Main Street, Cambridge, MA 02142 (US). MAS¬ kind of regional protection available): ARIPO (BW, GH, SACHUSETTS INSTITUTE OF TECHNOLOGY GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, [US/US]; 77 Massachusetts Ave., Cambridge, MA 02142 TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (US). TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (72) Inventor: HEIMAN, Myriam; 33 Eliot Memorial Road, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Newton, MA 02458 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). [Continued on nextpage] (54) Title: COMPOSITIONS, METHODS AND USE OF SYNTHETIC LETHAL SCREENING (57) Abstract: The present invention generally relates to methods of identify ing modulators of central nervous sys tem diseases and the use of the modul ators in treatment and diagnosis. The Lentiviral libra methods utilize a novel high through put screen that includes injection of a library of barcoded viral vectors ex pressing shRNA's, CRISPR/Cas sy s tems or cDNA's into animal models of disease and detecting synthetic lethal ity. w o 2016/069591 A : llll II II 11III III II II I II 11II IIII II I II Published: — without international search report and to be republished upon receipt of that report (Rule 48.2(g)) COMPOSITIONS, METHODS AND USE OF SYNTHETIC LETHAL- SCREENING RELATED APPLICATIONS AND INCORPORATION BY REFERENCE [00 This application claims benefit of and priority to US provisional patent application Serial No. 62/122,686, filed October 27, 2014. [0002] The foregoing applications, and all documents cited therein or during their prosecution ("appln cited documents") and all documents cited or referenced in the app n cited documents, and all documents cited or referenced herein ("herein cited documents"), and all documents cited or referenced in herein cited documents, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference. FEDER AL FUNDING LEGEND [0003] This invention was made with government support under grant number N808588Q awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD OF THE INVENTION [0004] The present invention generally relates to methods of identifying modulators of central nervous system diseases using a novel high throughput methodology that includes expressing CRISPR/Cas systems, shRNA's or cDNA's in animalmodels of disease. BACKGROUND OF THE INVENTION [0005] Currently there are no cures or effective treatments for many neurodegenerative diseases. All of the major neurodegenerative diseases display characteristic nerve-cell (neuronal ) vulnerability patterns, as well as an increased prevalence with advanced age. Many genes are involved in the pathogenesis of such diseases. As such, it is a challenge to find genes that are modulators of disease pathogenesis that can be used for diagnostic screening or effective treatments. [0 06] One such disease is Huntington's Disease. Huntington's disease, the most common inherited neurodegenerative disease, is characterized by a dramatic loss of deep-layer cortical I and striatal neurons, as well as morbidity in mid-life. Huntington's disease is the most common genetic cause of abnormal involuntary writhing movements called chorea. [ ΘΘ7] Symptoms of the disease can vary between individuals and even among affected members of the same family, but usually progress predictably. The earliest symptoms are often subtle problems with mood or cognition. A general lack of coordination and an unsteady gait often follows. As the disease advances, uncoordinated, jerky body movements become more apparent, along with a decline in mental abilities and behavioral symptoms. Physical abilities are gradually impeded until coordinated movement becomes very difficult. Mental abilities generally decline into dementia. Complications such as pneumonia, heart disease, and physical injury from fa ls reduce life expectancy to around twenty years from the point at which symptoms begin. There is no cure for Huntington's disease, and full-time care is required in the later stages of the disease. [0008] Treatments for Huntington's disease are available to reduce the severity of some of its symptoms (Frank et al., (2010) Drugs 70 (5): 561-71). Tetrabenazine was approved in 2008 for treatment of chorea in Huntington's disease in the United States. Other drugs that help to reduce chorea include neuroleptics and benzodiazepines. Compounds such as amantadine are still under investigation but have shown preliminary positive results (Walker, (2007) Lancet 369 (9557): 218-28). Hypokinesia and rigidity, especially in juvenile cases, can be treated with anti- Parkinson drugs, and myoclonic hyperkinesia can be treated with valproic acid. [0009] Huntington's disease is caused by a mutation in the Huntingtin gene. Expansion of a CAG (eytosme-adeiime-guamne) triplet repeat stretch within the Huntingtin gene results in a mutant form of the protein, whi c gradually damages cells in the brain, through mechanisms that are not fully understood. The length of the trinucleotide repeat accounts for 60% of the variation in the age symptoms appear and the rate they progress. The remaining variation is due to environmental factors and other genes that influence the mechanism of the disease (Walker, (2007) Lancet 369 (9557): 218-28). [0010] The diagnosis of Huntington's disease is suspected clinically in the presence of symptoms. The diagnosis can be confirmed through molecular genetic testing which identifies the expansion in the Huntingtin gene. Testing of adults at risk for Huntington disease who have no symptoms (asymptomatic) of the disease has been available for over ten years. However, this testing cannot accurately predict the age a person found to carry a Huntington disease causing mutation will begin experiencing symptoms, the severity or type of symptoms they will experience, or rate of disease progression. Other markers for disease progression are available, for example, loss of DARPP-32 striatal expression has been shown to be a molecular marker of Huntington's disease progression (Bibb et a!., (2000) Proc Natl Acad Sci 6;97(12):6809-14). [ ΘΙ 1] Human genetic studies led to the identification of huntingtin as the causative gene. Recent genomic advances have also led to the identification of hundreds of potential interacting partners for huntingtin protein, and many hypotheses as to the molecular mechanisms whereby mutant huntingtin leads to cellular dysfunction and death (Goehler et al., (2004) Mo . Cell 15 (6): 853-65). Huntingtin protein is expressed in all mammalian cells and interacts with proteins which are involved in transcription, cell signaling and intracellular transporting (Harjes et al., (2003) Trends Biochem. Sci. 28 (8): 425-33). However, the multitude of possible interacting partners and cellular pathways affected by mutant huntingtin has obfuscated research seeking to understand the etiology of this disease, and to date no curative therapeutic exists for the disease. [ Θ12] A high throughput screening method to discover modulators of diseases such as Huntington's disease, is a powerful tool to identify new drug targets, new prognostic methods, and new treatments. [0013] Citation or identification of any document i this application is not an admission that such document is available as prior art to the present invention. SUMMARY OF THE INVENTION [0Θ14] It is an object of the invention to provide a genetic screening platform that could be used in mammals to identify modulators of diseases of the central nervous system. It is another object of the invention that the modulators are used in treatments,
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