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WO 2018/078031 Al 03 May 2018 (03.05.2018) W !P O PCT

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WO 2018/078031 Al 03 May 2018 (03.05.2018) W !P O PCT (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 2018/078031 Al 03 May 2018 (03.05.2018) W !P O PCT (51) International Patent Classification: C12N 5/071 (2010.01) A61P 17/00 (2006.01) A61K 38/08 (2006.01) (21) International Application Number: PCT/EP20 17/077479 (22) International Filing Date: 26 October 2017 (26.10.2017) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 16196264.2 28 October 2016 (28.10.2016) EP (71) Applicant: ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE (EPFL) [CH/CH]; EPFL-TTO, EPFL In novation Park J, 1015 Lausanne (CH). (72) Inventors: ZAFFALON, Andrea; c/o EPFL-TTO, Quarti- er de l'Innovation - J, 1015 Lausanne (CH). BARRAN- DON, Yann; c/o EPFL-TTO, Quartier de l'Innovation - J, 1015 Lausanne (CH). (74) Agent: KATZAROV SA; 19 rue des Epinettes, 1227 Geneve (CH). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 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, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 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, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: — with international search report (Art. 21(3)) o 00 © 00 (54) Title: METHODS OF DERIVATION AND/OR PROPAGATION OF EPITHELIAL CELLS © (57) Abstract: The present invention relates to methods of derivation and/or propagation of epithelial cells from tissue comprising culturing said tissue in media containing an effective amount of a proprotein convertase inhibitor for a period of time allowing the derivation and/or propagation of epithelial cells. Methods of derivation and/or propagation of epithelial cells FIELD OF THE INVENTION The present invention relates to methods of derivation and/or propagation of epithelial cells from tissue comprising culturing said tissue in media containing an effective amount of a proprotein convertase inhibitor for a period of time allowing the derivation and/or propagation of epithelial cells. BACKGROUND OF THE INVENTION Today, there is a need in regenerative medicine to improve the therapies for epithelial cell associated diseases and injuries. The use of these genes products or small molecules, independently or in combination, will improve the process of ex-vivo amplification for autologous and homologous cell based therapies. It will also be of interest for the development of therapeutic agents to enhance healing of epithelia such as the skin, cornea, oral and nasal mucosa etc. There is also a need for the development of robust in vitro systems to study normal epithelial cells (ex: skin keratinocytes, corneal epithelial cells etc.). The current state of the art for the culture of human epithelial stem cells (skin, cornea and other stratified epithelia) involves the use of feeder cells (3T3 cells). Those cells were derived from mouse embryo in the laboratory of Howard Green (Todaro and Green, 1963). When cell cycle arrested (by irradiation or mitomycin c treatment), feeder cells can support the growth of human epithelial cells and allow to produce enough autologous material to treat large burn wounds (Gallico et al., 1984; Rheinwald and Green, 1975). However, the regulatory authorities constantly push towards the development of alternatives to get rid of the "xeno" component of the system (Feeder cells and serum). BRIEF DESCRIPTION OF THE FIGURES Figure 1 represents 3T3-J2 feeder cells (MEFs) and the Cultured Epidermal Autografts (CEA) procedure. Figure 2 depicts the screening procedure. Figure 3 shows the effects produced by inhibition of FURIN with a small molecule (Proprotease convertase inhibitor). FURIN inhibition reduces the signal of the rhodamine B fluorescence assay. Figure 4 shows the results of the QPCR analysis of the expression of DNp63, HOPX, LEKTI, IVL and KRT1 . It also shows the results of the quantification of KI67 positive cells by immunofluorescence analysis. DESCRIPTION OF THE INVENTION To identify the genes involved in the cross-talk between 3T3-J2 cells and human keratinocytes stem cells, the Inventors decided to screen the 3T3 cells with the mouse druggable genome siRNA library (QIAGEN). The library covered only 8'320 genes from the mouse genome. To validate the results of the primary screen, a secondary screen for the same 126 genes was performed. Other genes expected to have an effect in the culture system (Table 1) were also included. For the secondary screen, both individual ("deconvolved"), and pools of siRNAs were tested in duplicates for each targeted gene. The secondary screen confirmed the effect for 70 genes (53 %) (Table 2). Table 1 Cdk2 12566 Ces3b 13909 Clec2d 93694 Csnklal 93687 Ctdsp2 52468 Dctnl 13191 Ddx39 68278 Ddx54 71990 Ddx58 230073 DII3 13389 DII4 54485 Dmbtl 12945 Dokl 13448 Dok2 13449 Dok5 76829 Efnal 13636 Egf 13645 Eglnl 112405 Ehd4 98878 Eif3c 56347 Emd 13726 Epb4.2 13828 Ercc2 13871 Ewsrl 14030 Exosc8 69639 Eya3 14050 Ezh2 14056 F10 14058 Fbxo31 76454 Fbxo34 78938 Fbxwll 103583 Fcrl5 329693 Fgf7 14178 Fhl5 57756 Fkbpla 14225 Fkbp8 14232 Flcn 216805 Ftmt 67634 Furin 18550 Fut8 53618 Fzd3 14365 GaBstl 53897 Gcdh 270076 Ggal 106039 Gjb2 14619 Gm5867 545756 Gnb5 14697 Gne 50798 Gpd2 14571 Gpnmb 93695 Gpx7 67305 Grial 14799 Gsn 227753 Hs3stl 15476 Htr4 15562 Htr6 15565 III f 9 215257 1120 58181 Il21r 60504 1125 140806 Itgav 16410 Kcnj9 16524 Lifr 16880 Lmo2 16909 Mapkl5 332110 Mapkapk2 17164 Mknkl 17346 Mllt6 246198 Mmplb 83996 Necab2 117148 Nefh 380684 Nfkbie 18037 Nrlh2 22260 Nsmf 56876 Olfrl301 258889 Olfr32 18331 Olfr684 244187 Olfr731 258360 Olfr888 258416 Olfr922 258777 Olfr95 258506 Pabpnl 54196 Papln 170721 Pccb 66904 Pdlim7 67399 Pfnl 18643 Pgam2 56012 Pkia 18767 Pkn3 263803 Pla2g2d 18782 Pld3 18807 Pole 18973 Porcn 53627 Ppan 235036 Ppil2 66053 Prss22 70835 Prss48 368202 Prtn3 19152 Psma6 26443 Psmb4 19172 Psmcl 19179 Psmc2 19181 Psmc5 19184 Psmd2 21762 Ptk2 14083 pl35 66489 Rpl38 67671 Rpl4 67891 Rrml 20133 Rrm2 20135 Sars 20226 Smc3 13006 Snrpdl 20641 Stat4 20849 Styxll 76571 Tbck 271981 Tgfbl 21803 Tsen2 381802 Tssk2 22115 Vmnlr45 22297 Wdr92 103784 Wnk4 69847 Wnt3 22415 Xab2 67439 Xpol 103573 Xpo7 65246 Table 2 Then, a functional annotation analysis with the DAVID bioinfornnatics resources (Huang et al., 2009) on the list of putative hits has been performed. Only 3 pathways were enriched (Table 3). Most of genes identified in the secondary screen are involved in different cellular processes. To sort the putative hits in a comprehensive list, the subcellular annotations from GeneCards® (http://www.genecards.org/ ) were retrieved. This allowed to identify putative "feeder" genes (transmembrane receptors, growth factors, transmembrane ligands and other signaling molecules that influence epithelial stem cells growth in vitro). Several genes associated with epidermal homeostasis and wound repair are represented. For example, IL20 is a cytokine that is upregulated in psoriasis (a disease characterized by a hyper proliferative epidermis) (Ouyang et al., 201 1) . MMP1 , a collagenase, is also upregulated in wounded skin and facilitates the migration of keratinocytes (Rohani et al., 2014). FURIN is also known to play a key role during wound repair (Gurtner et al., 2008). Table 3 In view of these findings, the present invention thus relates to methods of derivation and/or propagation of epithelial cells from tissue comprising culturing said tissue in media containing an effective amount of a modulator of i) one or more genes involved in epithelial cells propagation and/or differentiation, or of a ii) product of said genes for a period of time allowing the derivation and/or propagation of epithelial cells. Preferably, the one or more genes involved in epithelial cells propagation and/or differentiation will be selected from the group of gene listed in Table 1. Most preferably the one or more genes involved in epithelial cells propagation and/or differentiation will be selected from the group comprising DII3, DII4, Dmbtl , Efnal , Furin, Gpnmb, II20, Itgav, Lifr, Mapk1 5, Mmpl b, Papln and Smc3, or from a combination of one of more of these genes. Generally, the modulator will be selected from the group comprising a chemical agent, an antibody, an engineered protease, and enzymatically active RNA. The modulator can either activate or silence the genes or inhibit or activate the product of said genes. Most preferably, the enzymatically active RNA is selected from the group comprising a miRNA, a siRNA, a piRNA, a hnRNA, a snRNA, esiRNA, shRNA, decoys, RNA aptamers and an antisense oligonucleotide. One will appreciate that any compound with different formulations capable to inhibit or activate one or more physiological actions effected by a gene involved in epithelial cells propagation and/or differentiation is encompassed by the present invention.
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