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WO 2015/130968 A2 3 September 2015 (03.09.2015) P O P C T

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WO 2015/130968 A2 3 September 2015 (03.09.2015) P O P C T (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 2015/130968 A2 3 September 2015 (03.09.2015) P O P C T (51) International Patent Classification: Inc., 75 Francis Street, Boston, MA 021 15 (US). YOSEF, C12Q 1/68 (2006.01) Nir; 1520 Laurel Ave., Richmond, CA 94805 (US). (21) International Application Number: (74) Agents: KOWALSKI, Thomas J. et al; Vedder Price PCT/US20 15/0 17826 P.C., 1633 Broadway, New York, NY 1001 9 (US). (22) International Filing Date: (81) Designated States (unless otherwise indicated, for every 26 February 2015 (26.02.2015) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (25) Filing Language: English BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (26) Publication Language: English DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (30) Priority Data: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 61/945,641 27 February 2014 (27.02.2014) US MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (71) Applicants: THE BROAD INSTITUTE INC. [US/US]; PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 415 Main Street, Cambridge, MA 02142 (US). THE SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, BRIGHAM AND WOMEN'S HOSPITAL, INC. TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. [US/US]; 75 Francis Street, Boston, MA 021 15 (US). (84) Designated States (unless otherwise indicated, for every PRESIDENT AND FELLOWS OF HARVARD COL¬ kind of regional protection available): ARIPO (BW, GH, LEGE [US/US]; 17 Quincy Street, Cambridge, MA 02138 GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (US). MASSACHUSETTS INSTITUTE OF TECHNO¬ TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, LOGY [US/US]; 77 Massachusetts Ave., Cambridge, MA TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, 02142 (US). DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (72) Inventors: KUCHROO, Vijay; 30 Fairhaven Road, New LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, ton, MA 02149 (US). REGEV, Aviv; 53 Standish Street SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). #3, Cambridge, MA 02138 (US). GAUBLOMME, Jellert; 36 Oxford Street, GSAS Mailcenter Conant 104, Published: Cambridge, MA 02138 (US). LEE, Youjin; 360 Riverway, — without international search report and to be republished Apt. 9, Boston, MA 021 15 (US). SHALEK, Alexander, upon receipt of that report (Rule 48.2(g)) K.; 113 River Street, Unit 1, Cambridge, MA 02139 (US). WANG, Chao; c/o The Brigham and Women's Hospital, (54) Title: T CELL BALANCE GENE EXPRESSION, COMPOSITIONS OF MATTERS AND METHODS OF USE THEREOF < mRSA © (57) Abstract: This invention relates generally to compositions and methods for identifying the regulatory network that modulates, o controls or otherwise influences T cell balance, for example, Thl7 cell differentiation, maintenance and/or function, as well, com positions and methods for exploiting the regulatory network that modulates, controls or otherwise influences T cell balance in a vari ety of therapeutic and/or diagnostic indications. This invention also relates generally to identifying and exploiting target genes and/or target gene products that modulate, control or otherwise influence T cell balance in a variety of therapeutic and/or diagnostic indications. T CELL BALANCE GENE EXPRESSION, COMPOSITIONS OF MATTERS AND METHODS OF USE THEREOF RELATED APPLICATIONS AND INCORPORATION BY REFERENCE [0001 ] This application claims priority from US provisional patent application 61/945,641, filed February 27, 2014, incorporated herein by reference. Reference is made to WO/2012/048265; WO/2014/145631; WO/2014/134351. The foregoing applications, and all documents cited therein or during prosecution ("appln cited documents") and all documents cited or referenced in the appln cited docimieiits, and all documents cited or referenced herein ("herein cited documents"), and a ll 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. Appln cited documents, herein cited documents, ail documents herein referenced or cited, and all documents indicated to be incorporated herein by reference, are incorporated by reference to the same extent as if each individual document was specifically and individually set forth herein in full and indicated to be incorporated by reference when or where cited or referenced. FEDERAL FUNDING LEGEND [0 02 This invention was made with Government support under the following grants: Pioneer Grant DP1OD003958-01 awarded by National Institute of Health; Pioneer Grant DP1OD003958-03 awarded by National Institute of Health; Centers of Excellence in Genomics Science Grant 1P5GHGG06193-01 awarded by National Institute of Health; Grant P01HG005 062-01 awarded by National Human Genome Research Institute; Grant DP1OD003893 awarded by National institute of Health, Grant NS30843 awarded by National Institute of Health, Grant NS045937 awarded by National Institute of Health, Grant AI 73748 awarded by National Institute of Health, Grant AI45757 awarded by National Institute of Health, Grant P01AI056299 awarded by National Institute of Health and Grant RG2571 awarded by National MS Society, New York. The Government may have certain rights. FIELD OF THE INVENTION [ Θ03] This invention relates generally to compositions and methods for identifying the regulatory network that modulates, controls or otherwise influences T cell balance, for example, T 7 ceil differentiation, maintenance and/or function, as well compositions and methods for exploiting the regulatory network that modulates, controls or otherwise influences T cel balance i a variety of therapeutic and/or diagnostic indications. This invention a so relates generally to identifying and exploiting target genes and/or target gene products that modulate, control or otherwise influence T cell balance in a variety of therapeutic and/or diagnostic indications. BACKGROUND OF THE INVENTION [ Θ 4] Despite their importance, the molecular circuits that control the balance of T cells, including the differentiation of naive T cells, remain largely unknown. Recent studies that reconstructed regulatory networks in mammalian cells have focused on short-term responses and relied on perturbation-based approaches that cannot be readily applied to primary T cells. Accordingly, there exists a need for a better understanding of the dynamic regulatory network that modulates, controls, or otherwise influences T cell balance, including Thl7 cel differentiation, maintenance and function, and means for exploiting this network in a variety of therapeutic and diagnostic methods. Citations herein are not intended as an admission that anything cited is pertinent or prior art; nor does it constitute any admission as to the contents or date of anything cited. SUMMARY OF THE INVENTION [0005] The invention has many utilities. The invention pertains to and includes methods and compositions therefrom of Drug Discovery, as well as for detecting patients or subjects who may or may not respond or be responding to a particular treatment, therapy, compound, drug or combination of drugs or compounds; and accordingly ascertaining which drug or combination of drugs may provide a particular treatment or therapy as to a condition or disease or infection or infectious state, as well as methods and compositions for selecting patient populations (e.g., by detecting those who may or may not respond or be responding), or methods and compositions involving personalized treatment a combination of Drug Discovery and detecting patients or subjects who may not respond or be responding to a particular treatment, therapy, compound, drug or combination of drugs or compounds (e.g., by as to individuals), so detecting response, nor responding, potential to respond or not, and adjusting particular treatment, therapy, compound, drug or combination of drugs or compounds to be administered or administering a treatment, therapy, compound, drug or combination of drugs or compounds indicated from the detecting) [0006] The invention provides compositions and methods for modulating T cell balance, e.g., Thl7 cell differentiation, maintenance and function, and means for exploiting this network in a variety of therapeutic and diagnostic methods. As used herein, the term "modulating" includes up-regulation of, or otherwise increasing, the expression of one or more genes, down-regulation of, or otherwise decreasing, the expression of one or more genes, inhibiting or otherwise decreasing the expression, activity and/or function of one or more gene products, and/or enhancing or otherwise increasing the expression, activity and/or function of one or more gene products. [0007] As used herein, the term "modulating T cell balance" includes the modulation of any of a variety of T cell-related functions and/or activities, including by way of non-limiting example, controlling or otherwise influencing the networks that regulate T cell differentiation; controlling or otherwise influencing the networks that regulate T cell maintenance, for example, over the lifespan of a T cell;
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