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Tommune Touttmann TOMMUNEUS009952216B2TOUTTMANN (12 ) United States Patent ( 10 ) Patent No. : US 9 , 952 ,216 B2 Visel et al. (45 ) Date of Patent: Apr. 24 , 2018 ( 54 ) BRAIN - SPECIFIC ENHANCERS FOR C12N 15 / 86 (2006 .01 ) CELL -BASED THERAPY A61K 48 /00 (2006 .01 ) (52 ) U .S . CI. (71 ) Applicants :Axel Visel, El Cerrito , CA (US ) ; John CPC . .. .. GOIN 33 / 56966 (2013 .01 ) ; A61K 35 / 545 L . R . Rubenstein , San Francisco , CA ( 2013 .01 ) ; C12N 15 /85 ( 2013 .01 ) ; C12N (US ) ; Ying- Jiun ( Jasmine) Chen , 15 / 86 (2013 .01 ) ; GOIN 33/ 5014 ( 2013 .01 ) ; South San Francisco , CA ( US) ; Len A . A61K 48 / 00 ( 2013 .01 ) ; C12N 2830 /008 Pennacchio , Sebastopol, CA (US ) ; ( 2013 .01 ) Daniel Vogt, Burlingame, CA (US ) ; ( 58 ) Field of Classification Search Cory Nicholas, San Francisco , CA None (US ) ; Arnold Kriegstein , Mill Valley, See application file for complete search history . CA (US ) (56 ) References Cited ( 72 ) Inventors : Axel Visel , El Cerrito , CA ( US ) ; John L . R . Rubenstein , San Francisco , CA U . S . PATENT DOCUMENTS (US ) ; Ying - Jiun ( Jasmine ) Chen , 5 ,436 , 128 A * 7 /1995 Harpold . .. GOIN 33/ 6872 South San Francisco , CA (US ) ; Len A . 435 / 365 Pennacchio , Sebastopol, CA (US ) ; Daniel Vogt, Burlingame, CA (US ) ; OTHER PUBLICATIONS Cory Nicholas, San Francisco , CA (US ) ; Arnold Kriegstein , Mill Valley , Ferguson et al . The human synaptotagmin IV gene defines an CA (US ) evolutionary break point between syntenic mouse and human chro mosome regions but retains ligand inducibility and tissue specific ( 73 ) Assignee: The Regents of the University of ity . The Journal of Biological Chemistry , vol . 275 , No . 47 , pp . 36920 - 36926 , 2000 . * California , Oakland , CA (US ) Skottman et al . Gene expression signatures of seven individual human embryonic stem cell lines. Stem Cells , vol . 23 , pp . 1343 ( * ) Notice : Subject to any disclaimer , the term of this 1356 , 2005 . * patent is extended or adjusted under 35 De Vita et al. Flow cytometric and cytogenetic analyses in human U . S . C . 154 (b ) by 0 days . spontaneous abortions. Human Genetics , vol. 91, pp . 409 -415 , Jun . 1993 . * (21 ) Appl. No. : 14 /512 , 306 GenBank Accession No . AC044873 .13 , publicly available Oct . 2002 , printed as pp . 1 /40 -40 /40 . * (22 ) Filed : Oct . 10, 2014 * cited by examiner (65 ) Prior Publication Data Primary Examiner - Jennifer Dunston US 2015 /0044187 A1 Feb . 12 , 2015 ( 74 ) Attorney , Agent, or Firm — Kilpatrick Townsend & Stockton LLP Related U . S . Application Data (63 ) Continuation of application No . (57 ) ABSTRACT Herein are described a set of novel specific human enhancers PCT/ US2013 /036030 , filed on Apr. 10 , 2013 . for specific forebrain cell types used to study and select for (60 ) Provisional application No . 61 /622 ,467 , filed on Apr. human neural progenitor cells . This approach enables the 10 , 2012 , provisional application No . 61/676 , 606 , ability to generate interneurons from human ES , iPS and in filed on Jul. 27 , 2012 . cells , making them available for human transplantation and for molecular/ cellular analyzes. These approaches are also ( 51 ) Int. Ci. directly applicable to generating other neuronal cell types , C12N 15 /85 ( 2006 . 01 ) such as cortical and striatal projection neurons , which have GOIN 33/ 569 ( 2006 . 01) implications for many human diseases . GOIN 33 /50 ( 2006 .01 ) A61K 35 / 545 ( 2015 .01 ) 10 Claims, 32 Drawing Sheets U . S . Patent Apr . 24 , 2018 Sheet 1 of 32 US 9 ,952 , 216 B2 FIG . 1 ASSESSOSOS3126* 743624 * 59600 * 81224 fra 187 81161 * n8653 $ 1072 880 131025 $ 16604 9836 1987 15818 18103 $ * $ 1679 * 191537 ust z9 * hs 1626 * 98 10 : 9 * hs1230 183540 K $ 807 ks 1027 81092 6978 * $ 1187 $ 967 * * 1060 * 1166 .* h8923 ns1532 hs 156€ 1202181563 H: $622 69166* 1578 * * * 3102 880 1633 * 19914 1013 1546 81178 097588 4838 wiszyn ohsices usar genes pacated in thiencaphakor development or function : bbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbble Since www . Rhenis ) Swibo Serie 7817e hs0 & '7 '. ' ' ' ' 995' ' ' ' ' ' 'ASCUS ' ' W SchaeteW W -cute " " " " " "comodex " " " " " " " " " " "homoing " " " " 19 : 029 SMX ; Brasty sonces 3 : 09babox 3 391236 BMX erogty sprzdos koreobK 3433 25 En racerto . A $ 1823 FOXO forkvad 60X01 as : 983 resy Brairy and enhausMSX ? ta 1533 inhibics of ONA onda 457545 1. 68 minnoid arter binding factor 1 881361 EMOS L } & * orai Quixa as1024$ 177 ., ms16X15163714 . 24 rucea Fecior su 2 . Boom 9 : 579 07Xossistenticio horreddox 2 545 SOUZEY POUmair , Bass 3 . sünscricum factor } oCT in , f81035 68 ! 128 RU ones3 65x2 6181529 , 1481528 . $ POU 295 Xbox 3 Osta SOX2 SR box cordisaing go os1039 S2 353836 ansation facie ha1166 . 181538 WXXNX honaxx (31183 ) ht ? ? ? ? ? gea d & inte????????) see ? } \ $ 1873 2104 ac finger potes < $ * & Cazaust U . S . Patent Apr . 24 , 2018 Sheet 2 of 32 US 9 ,952 , 216 B2 FIG . 2 ? ? :*. 8886 09480 hs 192 F G DaDDOsim:;* VY.. VY - ns1050 h 1035 181345 h : 200 W M U 2002* * .. *! . *** 18218 hs 1358 8 969 81025 + 2 .000 S ns595 $ 123 h8871 19876 hs978 coac2mol . 0 229€115. 22 €13.5 h5840 1 81006 hs 1050 his 1172 MP, medial pallium ; OP, dorsal pallium ; LP, lateral pallium ; VP, ventralpallium ; LGE , lateral ganglionic eminence ; SeDES , septum U . S . Patent Apr. 24, 2018 Sheet 3 of 32 | US 9 ,952 ,216 B2 FiG . 3 |.3522 .22 . 2 . E*??? 3222285603 . animanawaran siations ?? . 22 . ? / * . ? ?? U . S . Patent Apr . 24 , 2018 Sheet 4 of 32 US 9 ,952 , 216 B2 FIG . 4 5 P = 0 . 0003 doenw en w ents 5 enhoe expected foldenrichment by ? naramenwwwwwwwwwwwwwwwwwwwwwwwwww ww WS AAYY .LYWW 10 709 408 103 norte overag of cr?? ??xpression and arcar activity ( forebrain subrogions , 1 * 81 enhancer. gene pairs ) wi :?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ? ??? ?? ?? ?? ?? ?? ?? ???? VUL4444444444444444444444 :. :. :. ooo rrrrrrrrrrr :. valdated hst16 QZ154$ 22 hs123 telencephalic * 1999999%mit enhancers gelos tiposPOLA1 chr : X * * * * * * * ** * * * ** * * Why www mwagana 25. OM0Mwana 26. M agnason25 28 . 2M21 yamanan 25 . 3M garan 25 AMAM U . S . Patent Apr . 24 , 2018 Sheet 5 of 32 US 9 ,952 , 216 B2 FIG . 4 . ' Lef1b81050 Wnt8b 181006 (ISH ) * (Lacz ) ( ISH ) (Lacz ) ES Nr211 08172 (ISH ) ( Lacz ) ( ISM ) * Lacz ) U . S . Patent Apr. 24, 2018 Sheet 6 of 32 | US 9 ,952 , 216 B2 FIG . 5A Telencephalon subregions -' * * ~ 2 2 ? ??? ?? 2_ ?}& {}"???? ?k ???? 13_S1_c F_502 -EZ! 1 S_5v2 d DAZAS? 13 *???? Enhances dC1a d) ? ?? 13 - ?| Z9S d????? ? -FOXSZ hs17 15112 ???152 his122014 , h?? ?????zs } s :}3hG322 } 1 2 }} } ? } 42 ? 32 22 ? } 39 452 48. ++ ?????{ ++ { ? ? ? 233 } _ ses } ?15 ?????7 1998 83 541??? ???33) t 2s886555 $ * . * * . * , h53? hs{ ?? ? 8? $ Fg! ! ! s5 s ? sts192 c , ?9 322? S123 }{ } { 4 h 2 ta 325 htts 21 } ht hs ; & S2 Y? ?? 3 ? ? htsS55 53 211 ???19 : 23 . .: : : 1 h687 1 11 242 -*: ?542 5 :: :: :: :: :: : 2 . 72. S341 s????????? + ? ?? ? $ $ - Sicilit s56 57 $ 435 ) 1 hs24 437328???$ 352?? 49 ? ht? 48 32 324 hs2444 44 . { \ c ak18 if; text U . S . Patent Apr . 24 , 2018 Sheet 7 of 32 US 9 ,952 , 216 B2 FIG . 5B Balliumwanaos OTX2_ Q3 CAT ;.. ?? . * LUKE OT . * . LI MKI_ CI . * . * . IL $T COAFP1_ 08 ** ersagsod-1} . 115 UM 01 * ..* * * .. !. 9801 ! wangunanna. $3 _ 01 ** !! wiwiwitinin AUC080 0 000 0004 0 .008 0 .012 Faise positive iste . 30 } ?1i { {{c ice Pallium and Subpallium? ?????????????????????????????????????????????????????????????????????????????????????????????????????? MZF \_ 04 Ceca 1 . 0 ** * ** * ** * ** , AP 1 , , , , , , SIE).BAISO-33351 , MZFL_ 02 , }, , , , , LH- X61, 01 , LUL - XB1_ 01 , { , HMBOX . 01 es , AVO - 092 0 .010 0. 0200 .080 * * * * * * * * * * * * * * * * * * * *. *. *. *. * . * . *. *. * *. * * # if 3 " : 0. 080 False -positive rate 10 ' ' ' ' ' ' ' ' ' ' ' ' ' Subpallium C CT mmmmmmmmmmmmmmmmmmmNEWROC_ 02 iiiiiiiiiiiiiiiiiiiinnnnnn *. *. LOT MOXAYO *. *. *. * *. ITT DLXZG OLEJBAINSoden *. *. 08 *. *. CACCIOLPQ6 . *. I MKX83_ 01 *. AUC078 . 0 000 2 .002 0 .001 0. 00€ 03. * * * * * * * * * * * * * * * * * * * * * * * * ** * * * * Modi portare 0 Faise positive rate 10 viiiiiiiiiiiiiiiiiiiiiiii VYYYYYYYYYYYYYYYYYYYYYYY View U . S . Patent Apr . 24 , 2018 Sheet 8 of 32 US 9 ,952 , 216 B2 FIG . 5C version Near D4/ SOXH : : : - fiear Es : : : 97ac2/siri gasverandi ein near GSX1 : : : : : : : : : : : : : m .near FOXG1 : * Luciferaseactivityfoldchangenormalizedtonegativecontrol : vor innear SPG/ SP8 : : : * ** vas auto the near ARX : *TRY : : : : : : : : 2 : L ana Positivens1340 ns304 4$ 669 1s532 8342 hs110 #$1321 His545 hs1052 1$1041 1151226 bs1027 His1007 TTELSE h9408 tys1187 69704 hs1019 Control Enhancer Enhancer Reporter Construct emancantho PGL4 .23 Luciferase Dlx2 Co - transfected with activator TF Ascl1 in PCAGGS, P19 cells U . S . Patent Apr . 24 , 2018 Sheet 9 of 32 US 9 ,952 , 216 B2 FIG . 6 plane a { rostral) plane b (caudal ) on www n . irene *** o LGE * SA? . :,-** OS-rti???? * * pallial ( dorsal structures : diencephalon : Memedial pallium Ththalamus OP dorsal pallium EMT errinentia thalami Plateral palium Vo ventral pallun CP choroid plexus differntatiof zics: Subpaliel ( ventral) structures mante zone (MZ ) UGE - latera gangliomic eminence subventricular zona (SVZ ) NGE medial ganglionio ainence Se Septum verticular zona (VZ ) POA - preoptic area U . S . Patent Apr. 24 , 2018 Sheet 10 of 32 US 9 , 952 , 216 B2 FIG . 7 pallium pallium and subpalliumn
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