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WO 2016/164463 Al 13 October 2016 (13.10.2016) P O P C T

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WO 2016/164463 Al 13 October 2016 (13.10.2016) 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 2016/164463 Al 13 October 2016 (13.10.2016) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07H 21/04 (2006.01) C12N 15/113 (2010.01) kind of national protection available): AE, AG, AL, AM, C07H 21/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) Number: International Application DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US20 16/0262 18 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 6 April 2016 (06.04.2016) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/144,219 7 April 2015 (07.04.2015) kind of regional protection available): ARIPO (BW, GH, 62/168,528 29 May 2015 (29.05.2015) GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 62/181,083 17 June 2015 (17.06.2015) TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicant: THE GENERAL HOSPITAL CORPORA¬ DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, TION [US/US]; 55 Fruit Street, Boston, Massachusetts LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, 021 14 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventors: LEE, Jeannie T.; 185 Cambridge St., Boston, Massachusetts 021 14 (US). MINAJIGI, Anand; 185 Published: Cambridge St., Boston, Massachusetts 021 14 (US). CAR- — with international search report (Art. 21(3)) RETTE, Lieselot; Boereweg 6, 8730 Beernem (BE). — with sequence listing part of description (Rule 5.2(a)) (74) Agents: DEYOUNG, Janice Kugler et al; Fish & Richardson P.C., P.O. Box 1022, Minneapolis, Minnesota 55440-1022 (US). (54) Title: METHODS FOR REACTIVATING GENES ON THE INACTIVE X CHROMOSOME LUC 450 400 350 300 250 200 50 no aza + control xist + aza FIG. 8A (57) Abstract: Methods for reactivating genes on the inactive X chromosome that include administering one or both of a DNA methyltransferase (DNMT) Inhibitor and/or a topoisomerase inhibitor, e.g., etoposide and/or 5-azacytidine (aza), optionally in com bination with an inhibitor of XIST RNA and/or an Xist-interacting protein, e.g., a chromatin-modifying protein, e.g., a small mo lecule or an inhibitory nucleic acid (such as a small inhibitory RNA (siRNAs) or antisense oligonucleotide (ASO)) that targets XIST RNA and/or a gene encoding an Xist-interacting protein, e.g., a chromatin-modifying protein. METHODS FOR REACTIVATING GENES ON THE INACTIVE X CHROMOSOME CLAIM OF PRIORITY This application claims the benefit of U.S. Patent Applications Serial Nos. 62/144,219, filed on April 7, 2015; 62/168,528, filed on May 29, 2015; and 62/181,083, filed on June 17, 2015. The entire contents of the foregoing are hereby incorporated by reference. FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with Government support under Grant Nos. R01- DA-38695 and R03-MH97478 awarded by the National Institutes of Health. The Government has certain rights in the invention. TECHNICAL FIELD Described herein are methods for reactivating genes on the inactive X chromosome that include administering one or both of a DNA methyltransferase (DNMT) Inhibitor and/or a topoisomerase inhibitor, e.g., etoposide and/or 5'- azacytidine (aza), optionally in combination with an inhibitor of Xist RNA and/or an Xist-interacting protein, e.g., a chromatin-modifying protein, e.g., a small molecule or a nucleic acid such as a small inhibitory RNA (siRNAs), e.g., an antisense oligonucleotide (ASO), e.g., locked nucleic acid (LNA), that targets Xist RNA and/or a gene encoding an Xist-interacting protein, e.g., a chromatin-modifying protein. BACKGROUND X chromosome inactivation (XCI) achieves dosage balance in mammals by repressing one of two X chromosomes in females. X-linked diseases occur in both males and females. In males, X-linked mutations result in disease because males carry only one X-chromosome. In females, disease occurs when a defective gene is present on the active X chromosome (Xa). In some cases, a normal, wild type copy of the gene is present on the inactive X chromosome (Xi), and the severity of the disease may depend on the prevalence (skewing) of inactivation of the X chromosome carrying the wild type gene. The invention described herein may be utilized to treat both male and female X-linked disease. In both females and males, upregulation of a hypomorphic or epigenetically silenced allele may alleviate disease phenotype, such as in Fragile X Syndrome. In females, reactivating a non-disease silent allele on the Xi would be therapeutic in many cases of X-linked disease, such as Rett Syndrome. SUMMARY Provided herein are methods and compositions for reactivating genes on the inactive or active X chromosome. Provided herein are compositions comprising a DNMT Inhibitor and/or topoisomerase inhibitor, and optionally an inhibitor of XistRNA and/or an Xist- interacting protein. Also provided herein are methods for activating an inactive X-linked allele in a cell, preferably a cell of a female heterozygous subject or a male hemizygous subject. The methods include administering to the cell (i) one or both of a DNA methyltransferase (DNMT) Inhibitor and/or a topoisomerase inhibitor; and optionally (ii) an inhibitor of Xist RNA and/or an Xist-interacting protein. As used herein, "an inhibitor of an Xist-interacting protein" can include one or more inhibitors, e.g., one or more small molecules or inhibitory nucleic acids. As used herein, "an inhibitor of XistRNA" can include one or more inhibitors, e.g., one or more small molecules or inhibitory nucleic acids, e.g., an antisense oligonucleotide (ASO), e.g., locked nucleic acid (LNA), that target XIST RNA or a gene encoding XIST RNA. In addition, provided herein are methods for activating an epigenetically silenced or hypomorphic allele on the active X-chromosome, e.g., FMRI, in a cell, e.g., in a cell of a male or female heterozygous subject. The methods include administering to the cell (i) one or both of a DNA methyltransferase (DNMT) Inhibitor and/or a topoisomerase inhibitor; and optionally (ii) an inhibitor of Xist RNA and/or an Xist-interacting protein. Also provided here are a DNMT Inhibitor and/or topoisomerase inhibitor, and optionally an inhibitor of Xist and/or an Xist-interacting protein, for use in activating an inactive X-linked allele in a cell, preferably a cell of a female heterozygous subject, preferably wherein the inactive X-linked allele is associated with an X-linked disorder. Also provided here are a DNMT Inhibitor and/or topoisomerase inhibitor, and optionally an inhibitor of Xist RNA and/or an Xist-interacting protein, for use in activating an epigenetically silenced or hypomorphic allele on the active X chromosome in a cell, either in a female heterozygous or male hemizygous subject, preferably wherein the active X-linked allele is associated with an X-linked disorder. Also provided here are a DNMT Inhibitor and/or topoisomerase inhibitor, and optionally an inhibitor of Xist RNA and/or an Xist-interacting protein, for use in treating an X-linked disorder in a female heterozygous or male hemizygous subject. In some embodiments of the methods or compositions described herein, the inhibitor of Xist RNA is an inhibitory nucleic acid that targets the Xist IncRNA, e.g., e.g., an antisense oligonucleotide (ASO), e.g., locked nucleic acid (LNA), or that targets a gene encoding XIST. In some embodiments of the methods or compositions described herein, the inhibitor of an Xist-interacting protein inhibits a protein described herein, e.g., shown in Tables 5 or 6 or 7, e.g., SMCla; SMC3; WAPL, RAD21; KIF4; PDS5a/b; CTCF; TOPI; TOP2a; TOP2b; SMARCA4 (BRG1); SMARCA5; SMARCC1; SMARCC2; SMARCB1; RINGla/b (PRC1); PRC2 (EZH2, SUZ12, RBBP7, RBBP4, EED); AURKB; SPEN/MINT/ SHARP; DNMT1; SmcHDl; CTCF; MYEF2; ELAV1; SUN2; Lamin-B Receptor (LBR); LAP; hnRPU/SAF-A; hnRPK; hnRPC; PTBP2; RALY; MATRIN3; MacroH2A; and ATRX. In some embodiments of the methods or compositions described herein, the inhibitor of an Xist-interacting protein is a small molecule inhibitor or an inhibitory nucleic acid that targets a gene encoding the Xist-interacting protein. In some embodiments, the inhibitor of an Xist-interacting protein is a small molecule inhibitor of cohesin or a cohesin subunit, e.g., a small molecule inhibitor of ECO-I or HDAC6, e.g., PCI34051, tubacin, apicidin, MS275, TSA, or saha. In some embodiments of the methods or compositions described herein, the inactive X-linked allele is associated with an X-linked disorder, and the DNMT Inhibitor and/or topoisomerase inhibitor, and the optional inhibitor of Xist RNA and/or Xist-interacting protein, are administered in a therapeutically effective amount. In some embodiments of the methods or compositions described herein, the active X-linked allele is associated with an X-linked disorder, and the DNMT Inhibitor and/or topoisomerase inhibitor, and the optional inhibitor of Xist RNA and/or Xist-interacting protein, are administered in a therapeutically effective amount.
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