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WO 2011/043591 A2 14 April 2011 (14.04.2011) PCT

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WO 2011/043591 A2 14 April 2011 (14.04.2011) PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau I (10) International Publication Number (43) International Publication Date WO 2011/043591 A2 14 April 2011 (14.04.2011) PCT (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12N 5/071 (2010.01) C12N 5/02 (2006.01) kind of national protection available): AE, AG, AL, AM, C12N 5/07 (2010.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) Number: International Application DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/KR20 10/006832 HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, 6 October 2010 (06.10.2010) MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, (25) Filing Language: English SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, (26) Publication Language: English TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 10-2009-0094854 6 October 2009 (06. 10.2009) KR kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, (71) Applicant (for all designated States except US): SNU ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, R&DB FOUNDATION [KR/KR]; San 56-1, Sillim- TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, dong, Gwanak-gu, Seoul 15 1-742 (KR). EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (72) Inventor; and SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (71) Applicant : KIM, Ji Yeon [KR/KR]; 118-1003, Banpo GW, ML, MR, NE, SN, TD, TG). Xi Apt., Banpo- ldong, Seocho-gu, Seoul 137-930 (KR). Published: (72) Inventor; and (75) Inventor/Applicant (for US only): PARK, Sung Sup without international search report and to be republished [KR/KR]; 114-405, Jugong Apt., Banpo-dong, Seocho- upon receipt of that report (Rule 48.2(g)) gu, Seoul 137-040 (KR). with sequence listing part of description (Rule 5.2(a)) (74) Agent: SON, Min; HANOL Intellectual Property & Law, 6th Floor, City Air Tower, 159-9 Samseong-dong, Gang- nam-gu, Seoul 135-973 (KR). (54) Title: METHOD FOR DIFFERENTIATION INTO RETINAL CELLS FROM STEM CELLS < (57) Abstract: Disclosed is a method for inducing stem cells to differentiate into retinal cells at high yield within a short period of time, without gene implantation and co-culture with retinal tissues, by implementing a differentiation process similar to the in vivo o embryonic development in chemically defined conditions. Also, retinal cells including the photoreceptor cells and their progenitor cells, and various types of other retinal cells, generated according to the method, are disclosed. A composition comprising the reti nal cells and a method are provided for treating retinal degeneration-related diseases. The differentiated photoreceptor cells, when transplanted into degenerated or injured retinas, can be engrafted and fused within the retinas to prevent or cure retinal degenera tion. Description Title of Invention: METHOD FOR DIFFERENTIATION INTO RETINAL CELLS FROM STEM CELLS Technical Field [1] The present invention relates to a method for differentiating stem cells into retinal cells within a short period of time at high yield. More particularly, the present invention relates to a method for differentiating stem cells into neural retinal progenitor cells, photoreceptor cell precursors, photoreceptor cells and other retinal cells, by culturing in different media and time periods specifically adapted to differentiation steps. Also, the present invention is concerned with neural retinal progenitor cells, pho toreceptor cell precursors, photorecepror cells and other retinal cells generated according to the method, a composition for the treatment of retinal degeneration- related diseases, comprising the cells, and a method for the treatment of retinal de generation-related diseases using the composition. [2] Background Art [3] blindness is the medical condition of lacking visual perception for physiological or neurological reasons. As many as tens of millions of people, which accounts for 0.2-0.5% of the population of the world, are affected with blindness, and are suffering from great losses in personal, social and economical respects. Retinal photoreceptor degeneration is one of the more dominant etiologies of blindnees, caused innately or by other various factors, including retinal dysplasia, retinal degeneration, aged macular degeneration, diabetic retinopathy, retinitis pigmentosa, congenital retinal dystrophy, Leber congenital amaurosis, retinal detachment, glaucoma, optic neuropathy, and trauma. No drugs have been developed for the fundamental treatment of these diseases thus far. To date, the replacement of dysfunctional photoreceptor cells, the alpha and omega of these retinal diseases, with new ones is regarded as the only promising therapy. Photoreceptor cell implantation is thought to prevent blindness or recover imperfect eyesight by delaying or restraining retinal degeneration, regenerating de generated retina, and enhancing retinal functions. [4] Stem cells have become a candidate useful for cell therapy of retinal diseases including bone marrow stem cells (BMSC), cord blood stem cells, amniotic fluid stem cells, fat stem cells, retinal stem cells (RSC), embryonic stem cells (ESC), induced pluripotent stem cells (iPSC) and somatic cell nuclear transfer cells (SCNT). [5] No significant research results have been yet suggested regarding the differentiation of stem cells into retinal cells (particularly, photoreceptor cells) and cell therapy based thereon. The differentiation of these stem cells into retinal cells might make it possible 1) to guarantee an infinite cell source for efficient cell therapy, 2) to identify the differ entiation mechanism from embryonic cells and retinal progenitors into retinal cells, which has remained unclear, 3) to find retina differentiation-related genes and molecules and lesions thereby, 4) to understand the pathogenesis of retinal de generative diseases, and 5) to develop drugs for preventing retinal degeneration and protecting the retina. [6] Since the first establishment thereof, human embryonic stem cell lines have been suggested to have the ability to differentiate into various types of cells which are useful for the cellular therapy of various diseases. Human embryonic stem cells appear to have a high potential when it comes to allowing the accurate examination of pathogenetic mechanisms and supplying fresh cells that can substitute for dys functional cells in clinical treatment. The production of human ESC derived-retinal photoreceptor cells under a completely identified reproducible condition and the use thereof in transplantation would guarantee a highly potential and effective therapy for retinal photoreceptor cell-related diseases. It has been assumed that human ESC derived-cells will have the same properties and functions as did the cells formed that were formed through a normal differentiation processes. Based on this assumption, dif ferentiation has been induced under circumstances similar to those of the devel opmental stages to produce pancreatic hormone-expressing endocrine cells (D'Amour, et al., Nat. BiotechnoL, 2006; 24: 1392-401), neurons (Pankratz, et al., Stem Cells 2007; 25: 1511-20), muscle cells (Barberi et al., Nat. Med., 2007; 13: 642-8), and vascular endothelial cells (Wang, et al., Nat. BiotechnoL, 2007; 25: 317-8). Also, many attempts have been made to differentiate human ESC into photoreceptor cells which may be effectively used to treat retinal diseases, but this ended with failure for most cases. [7] In fact, differentiation into retinal progenitor cells from human embryonic stem cells is the greatest achievement made thus far in this field, but the differentiation of retinal progenitor cells into photoreceptor cells failed (differentiation rate of less than 0.01%) (Lamba, Proc. Natl. Acad. Sci. USA, 2006; 103: 12769-74). One report held that human embryonic stem cells were successfully induced to differentiate into pho toreceptor cells, but the method used therein requires more than 200 days in total for the differentiation, with a differentiation rate of as low as 8%, and thus is impossible to apply to the clinical treatment of blindness (Osakada et al., Nat. BiotechnoL, 2008; 26: 215-24). [8] Disclosure of Invention Technical Problem [9] Leading to the present invention, intensive and thorough research into the differ entiation of human ESC into photoreceptor cells, conducted by the present inventors, resulted in the finding that chemically defined, in vitro conditions for differentiation into photoreceptor cells, similar to in vivo conditions, allow human stem cells to dif ferentiate into photoreceptor cells at high yield within four weeks with neither gene implantation nor co-culturing with retinal tissues. Also, the finally differentiated cells were 260-fold higher in population than the starting human embryonic stem cells, and thus can be applied to clinical transplantation. [10] Solution to Problem [11] It is therefore an object of the present invention to provide a method for inducing stem cells to differentiate into retinal cells including a multitude of photoreceptor cells and progenitor cells thereof, at high yield within a short period
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