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Wo2017/132155 (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 2017/132155 Al 3 August 2017 (03.08.2017) P O P C T (51) International Patent Classification: (74) Agent: HUNTER-ENSOR, Melissa; c/o Greenberg A61K 45/00 (2006.01) C07K 16/18 (2006.01) Traurig LLP, One International Place, Boston, Massachu A61P 25/18 (2006.01) setts 021 10 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/US2017/014757 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (22) International Filing Date: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, 24 January 2017 (24.01 .2017) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, (26) Publication Language: English MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, (30) Priority Data: NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, 62/286,867 25 January 2016 (25.01.2016) US RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, (71) Applicants: PRESIDENT AND FELLOWS OF HAR¬ ZA, ZM, ZW. VARD COLLEGE [US/US]; 17 Quincy Street, Cam bridge, Massachusetts 02138 (US). CHILDREN'S MED¬ (84) Designated States (unless otherwise indicated, for every ICAL CENTER CORPORATION [US/US]; 55 Shattuck kind of regional protection available): ARIPO (BW, GH, Street, Boston, Massachusetts 021 15 (US). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (72) Inventors; and TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicants : MCCARROLL, Steven, A. [US/US]; c/o DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, President and Fellows of Harvard College, 17 Quincy LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Street, Cambridge, Massachusetts 02 138 (US). SEKAR, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Aswin [US/US]; c/o President and Fellows of Harvard GW, KM, ML, MR, NE, SN, TD, TG). College, 17 Quincy Street, Cambridge, Massachusetts Published: 02138 (US). CARROLL, Michael, C. [US/US]; c/o Chil dren's Medical Center Corporation, 55 Shattuck Street, — with international search report (Art. 21(3)) Cambridge, Massachusetts 021 15 (US). STEVENS, Beth — before the expiration of the time limit for amending the [US/US]; c/o Children's Medical Center Corporation, 55 claims and to be republished in the event of receipt of Shattuck Street, Boston, Massachusetts 021 15 (US). amendments (Rule 48.2(h)) (54) Title: METHODS AND COMPOSITIONS FOR DETECTING AND TREATING SCHIZOPHRENIA FIG. 1B C4A or C4B ...ThrLeuSerProVallleHisArg. C4B ...ACCCTCTCTCCAGTGATACATAGG . (57) Abstract: The invention provides methods of treating schizophrenia in a subject, including for example, administering to the subject an agent that inhibits expression or activity of a C4A polynucleotide or polypeptide. The invention also provides methods of identifying a subject having or at risk of developing schizophrenia involving measuring or detecting an alteration in the level, copy number, and/or sequence of complement component C4A or complement component C4B relative to a reference. METHODS AND COMPOSITIONS FOR DETECTING AND TREATING SCHIZOPHRENIA CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 62/286,867, filed January 25, 2016, the disclosure of which is incorporated herein by reference in its entirety. STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH This invention was made with government support under Grant Nos. ROl HG006855, UOl MH105641, and ROl MH077139 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND OF THE INVENTION Schizophrenia is a heritable psychiatric disorder involving impairments in cognition, perception and motivation that usually manifest late in adolescence or early in adulthood. The pathogenic mechanisms underlying schizophrenia are unknown, but observers have repeatedly noted pathological features involving excessive loss of gray matter and reduced numbers of synaptic structures on neurons. While treatments exist for the psychotic symptoms of schizophrenia, there is no mechanistic understanding of, nor effective therapies to prevent or treat, the cognitive impairments and deficit symptoms of schizophrenia, its earliest and most constant features. New methods of identifying and treating patients having or at risk of developing schizophrenia are urgently needed. SUMMARY OF THE INVENTION As described below, the present invention features compositions and methods for (i) identifying a subject having or at risk of developing schizophrenia, (ii) monitoring treatment for schizophrenia, and (iii) treating or preventing schizophrenia in a subject. In one aspect, the invention provides a method of treating schizophrenia in a subject. The method contains the step of administering to the subject an agent that inhibits the expression or activity of a complement component 4A (C4A) polypeptide or polynucleotide. In another aspect, the invention provides a method of treating a subject having a neurodegenerative disease or disorder characterized by increased levels, activity, or expression of a complement component 4A (C4A) polypeptide or polynucleotide (e.g. Alzheimer's Disease, glaucoma, or age-related macular degeneration) by administering to the subject an agent that inhibits the expression or activity of a complement component 4A (C4A) polypeptide or polynucleotide. In another aspect, the invention provides a method of reducing an interaction between a neuron and microglia and/or reducing synaptic elimination in a subject, the method involving the step of contacting a microglia or neuron (e.g., at a synapse) with an agent that inhibits the expression or activity of a complement component 4A (C4A) polypeptide or polynucleotide. In various embodiments, one or more of the microglia or neuron is contacted with the agent in vitro or in vivo (e.g., in a subject). In certain embodiments, engulfment of synapses by microglia is reduced. In some embodiments, the method involves administering an agent that inhibits the expression or activity of a complement component 4A (C4A) polypeptide or polynucleotide to the subject. In various embodiments, the agent is administered to the subject intrathecally. In various embodiments, the agent inhibits the expression or activity of a complement component 4A (C4A) polypeptide or polynucleotide. In some embodiments, the agent inhibits the expression or activity of a complement component 4B (C4B) polypeptide or polynucleotide. In some other embodiments, the agent does not inhibit the expression or activity of a complement component 4B (C4B) polypeptide or polynucleotide. In some embodiments, the agent is an antibody or an inhibitory nucleic acid. In certain embodiments, the antibody specifically binds an epitope containing the amino acid sequence PCPVLD. In particular embodiments, the antibody does not bind an epitope containing the amino acid sequence LSPVIH. In various embodiments of any one of the aspects delineated herein, the subject is human. In another aspect, the invention provides a method of treating schizophrenia in a pre selected subject, the method containing the step of administering a schizophrenia treatment to the subject, where the subject is pre-selected by detecting an increase in a level of a complement component 4A (C4A) polynucleotide or polypeptide, an increase in a combined level of C4A and complement component 4B (C4B) polynucleotide or polypeptide, an increase in copy number of complement component 4A (C4A), and/or an alteration in a sequence of C4A or C4B polynucleotide relative to a reference in a biological sample obtained from the subject. In yet another aspect, the invention provides a method of monitoring treatment progress in a subject having schizophrenia and administered with a schizophrenia treatment. The method contains the step of measuring a level of C4A polypeptide or polynucleotide or a combined level of C4A and C4B polypeptide or polynucleotide relative to a reference level in a biological sample obtained from the subject, where a decrease in the level or combined level indicates the subject is responsive to the schizophrenia treatment. In still another aspect, the invention provides a method of determining efficacy of a schizophrenia treatment in a subject. The method contains the step of measuring a level of C4A polypeptide or polynucleotide or a combined level of C4A and C4B polypeptide or polynucleotide relative to a reference level in a biological sample obtained from the subject, where a decrease in the level or combined level indicates the the schizophrenia treatment is efficacious. In another aspect, the invention provides method of characterizing a subject having a mental disorder. The method contains the step of measuring a level of a complement component 4A (C4A) polynucleotide or polypeptide, a combined level of C4A and complement component 4B (C4B) polnucleotide or polypeptide, a copy number of C4A polynucleotide, and/or a sequence of C4A and/or C4B polynucleotide relative to a reference in a biological sample obtained from the subject, where an increase in the level of C4A polynucleotide
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