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Wo 2010/033906 A2 (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 25 March 2010 (25.03.2010) WO 2010/033906 A2 (51) International Patent Classification: (74) Agents: RESNICK, David et al; Nixon Peabody LLP, C12N 5/074 (2010.01) 100 Summer Street, Boston, Massachusetts 021 10 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/US2009/057669 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (22) International Filing Date: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, 2 1 September 2009 (21 .09.2009) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (26) Publication Language: English ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (30) Priority Data: NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, 61098683 19 September 2008 (19.09.2008) US SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant (for all designated States except US): PRESI¬ DENT AND FELLOWS OF HARVARD COLLEGE (84) Designated States (unless otherwise indicated, for every [US/US]; 17 Quincy Street, Cambridge, Massachusetts kind of regional protection available): ARIPO (BW, GH, 02138 (US). GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, (72) Inventors; and TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, (75) Inventors/Applicants (for US only): ICHIDA, Justin ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, [US/US]; 27 1 Dartmouth Street, Apartment 3C, Boston, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, Massachusetts 021 16 (US). BLANCHARD, Joel TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, [US/US]; 27 Fickett Road, Pownal, Maine 04069 (US). ML, MR, NE, SN, TD, TG). LAM, Kelvin [US/US]; 1188 Massachusetts Avenue, Ar lington, Massachusetts 02476 (US). RUBIN, Lee Published: [US/US]; c/o Harvard Stem Cell Institute, 77 Divinity — without international search report and to be republished Avenue, Cambridge, Massachusetts 021 38 (US). upon receipt of that report (Rule 48.2(g)) EGGAN, Kevin [US/US]; 181 Essex Street, Apartment E402, Boston, Massachusetts 021 11 (US). (54) Title: EFFICIENT INDUCTION OF PLURIPOTENT STEM CELLS USING SMALL MOLECULE COMPOUNDS inhibitor) 3 mM FIG. W (57) Abstract: The disclosure features a method of producing a reprogrammed cell (e.g. an induced pluripotent stem cell or an un differentiated cell) from a differentiated (e.g. somatic) cell. In some embodiments, the methods includes contacting a differentiated (e.g. somatic cell) with a TGFBRl inhibitor or anti-TGF- β-antibody to produce a reprogrammed cell (e.g. pluripotent stem cell or undifferentiated cell). Embodiments of the present invention relate to a reprogrammed cell and methods and compositions for pro ducing a chemically produced reprogrammed cell or populations thereof. EFFICIENT INDUCTION OF PLURIPOTENT STEM CELLS USING SMALL MOLECULE COMPOUNDS FIELD OF INVENTION [001] The invention relates to methods and compositions for reprogramming a differentiated cell into an undifferentiated cell, eg., an induced pluripotent cell or a partially induced pluripotent cell Embodiments of the present invention relate to a reprogrammed cell and methods and compositions for producing a chemically produced reprogrammed cell CROSS REFERENCE TO RELATED APPLICATIONS [002] This application claims the benefit under 35 U.S.C 119(e) of U.S. Provisional Patent Application Serial No: 61/098,683 filed September 19, 2008, the contents of which is incorporated herein in its entirety by reference. GOVERNMENT SUPPORT [003] This invention is made with Government Support under Grant No: HD046732-01Al awarded by the National Institutes of Health (NIH). The Government has certain rights in the invention. BACKGROUND OF THE INVENTION [004] One goal of regenerative medicine is to be able to convert an adult differentiated cell into other cell types for tissue repair and regeneration. Retroviral transduction with three genes: Sox2, Oct4, and Klf4, has been shown to directly reprogram mouse or human differentiated cells (e.g somatic cells) to a pluripotent stem cell state (1-5) Unfortunately, the resulting induced pluripotent stem (iPS) cells are suboptimal for uses in transplantation medicine and disease modeling because the viral transgenes they contain may spontaneously re-activate, a process that has lead to tumor formation in mice generated from iPS cells (6) Furthermore, in two gene therapy trials, the retroviral vectors used for delivery of reprogramming genes were themselves shown to be intrinsically oncogenic (7, 8). [005] While generation of iPS cells using non-integrating DNA-based methods (9-13) have been reported and are an improvement over retroviral delivery of reprogramming factors, use of such methods in therapeutic transplantation medicine and disease models is limited because these vectors are still considered to cause permanent alterations in chromosomal DNA (13, 14) that may be difficult to detect Therefore, the clinical implementation of reprogramming technology would optimally avoid viral transduction and the introduction of any transgenic DNA in general. While transduction with recombinant protein factors has been reported to be capable of reprogramming mouse embryonic fibroblasts (75), use of protein factors is limited due to this process is highly inefficient and too laborious and expensive to implement at a large-scale Furthermore, this methodology requires the use of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor that can cause long-lasting, heritable changes in the expression of imprinted and cancer-related genes in mammalian cells (16, 17). [006] The identification of small molecules that can efficiently reprogram patient cells without the use of DNA expression vectors or large-scale protein preparations might most reproducibly allow the efficient generation of pluripotent stem cells that would be genetically unmodified, and as a result, most suitable for use in cell therapies Small molecules that globally alter chromatin structure, including the DNA methyltransferase inhibitor 5-aza- cytidine (AZA) and the HDAC inhibitor VPA, can increase reprogramming efficiency and even reduce the number of factors required for reprogramming (18-21) Treatment with these inhibitors relaxes the structure of chromatin and in turn lowers the barrier to activation of endogenous pluπpotency associated genes However, Oct4 and Sox2 not only collaborate in reprogramming by activating genes required for pluripotency, they also function to repress genes promoting differentiation. It is therefore unlikely that this class of small molecules will alone be sufficient to replace all of the transgenic factors required for reprogramming. As a result, there is a significant need to identify additional small molecules that can function in reprogramming either independently or in concert with chemicals modulating chromatin structure. These reprogramming molecules might function through two broad mechanisms: to either activate expression of the endogenous reprogramming genes or to complement the omission of a transgenic factor, for instance by activating alternative genes that can substitute for them. Finally, identification of small molecules capable of reprogramming cells may provide additional insight regarding cytoplasmic signaling pathways that regulate pluripotency (22) [007] Reprogramming differentiated cells to a pluπpotent state could generate a rich supply of patient-specific stem cells for regenerative medicine. Recent work has demonstrated that exogenous nucleic acid expression of four transcription factors- Sox-2, Oct-4, KIf-4, and c-Myc, or Sox-2, Oct-4, Nanog, and Lin-28, can directly reprogram differentiated cells to a pluripotent stem cell state. [008] Neural stem cells (NSCs) that already express endogenous Sox-2 can be reprogrammed without retrovirally delivered Sox-2, but in the presence of the other exogenous expressed transcription factors. This approach may be capable of partially eliminating the viral transgenes, but it is unlikely that these or any other Sox-2-expressing cells will be readily accessible from patients. [009] It has been shown that small molecule inhibitors of DNA methyltransferases such as 5-aza-Cytidine (5azaC) orhistone deacetylases (HDACs) such as valproic acid (VPA), can increase reprogramming efficiency with all four factors or just three of the factors. However, in reprogramming experiments, these small molecules do not appear to replace the reprogramming factors, but instead increase their overall efficiency. Therefore, it may not be possible to replace all four reprogramming genes with these types of chemicals. Instead, it will likely require small molecules that perturb specific cell signaling pathways that result in the endogenous expression of the reprogramming genes or genes that substitute for them SUMMARY OF THE INVENTION [0010] The present invention relates to methods and compositions and compounds for reprogramming a differentiated cell In particular, the present invention relates to methods and compositions to reprogram a differentiated cell by contacting the differentiated cell with a molecule, such as a small molecule, without the need to use exogenous
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