Topic: A sustainable European induced pluripotent stem cell platform

Transcription

1 Tpic: A sustainable Eurpean induced pluriptent stem cell platfrm All infrmatin regarding future IMI Call tpics is indicative and subject t change. Final infrmatin abut future IMI Calls will be cmmunicated after apprval by the IMI Gverning Bard. Tpic details Actin type Submissin & evaluatin prcess Research and Innvatin Actin (RIA) 2 Stages Specific challenges t be addressed Since their intrductin in 2007 [1] human inducible pluriptent stem cells (human ipscs) have been rapidly and bradly incrprated int research t understand their ptential fr disease and are a very pwerful tl fr translatinal research. This has substantiated interest t incrprate this resurce int drug discvery pipelines, prspective patient stratificatin, recruitment fr clinical trials and pst-clinical drug assessment f safety issues fllwing rare event reprting. In additin, human ipscs can ptentially prvide unlimited autlgus cells fr therapy and therefre hld great prmise fr regenerative medicine [2]. The evlutin f these applicatins depends n facilitated and unfettered access t a standardised and well characterised ipsc resurce t help avid disseminatin f unauthenticated r substandard cell lines t the research cmmunity. ipscs are cells derived frm smatic cells f the bdy and reprgrammed by intrducing specific transcriptin factrs in rder t re-establish pluriptency [1] [3] ipscs can be differentiated intthe three germ layers, the mesderm, endderm, and ectderm, which frm the rgans during embrynic develpment. The cntinued ptimisatin f prtcls nw allws prducing large quantities f differentiated, human cells in a reliable and reprducible manner. Human ipscs are established frm patients with the prmise t capture in cell mdels specific human disease phentypes which cannt be revealed in animal mdels, and t allw studying these in a human cntext. With the advent f gene editing technlgies like the -Clustered Regularly Interspaced Shrt Palindrmic Repeats/assciated (Crispr/Cas)-system, specific mutatins relevant fr a certain disease are being intrduced int human ipscs t again mdel specific phentypes and cmpare with the isgenic parental line. While these effrts will freseeably imprve the cnsistency with which new cell lines will be develped they will nt necessarily fster the standardised and scalable distributin f pre-established r new lines t the wider hipsc research cmmunity. Tel +32 (0) Fax +32 (0) Pstal address: IMI JU TO Brussels Belgium infdesk@imi.eurpa.eu Visiting address: Ave de la Tisn d Or Brussels Belgium

2 The rising demand by academia and industry has instigated a number f large scale public and privately funded disease and/r ppulatin riented human ipsc banking initiatives in the US, Japan and UK [4]. Hwever, several issues shuld be vercme t advance the field quickly. First, it will be critical t netwrk ipsc resurces arund the wrld t create an ipsc library f bth nrmal and diseased cells using a cmmn quality standard. Secnd, a systematic apprach t develp an ipsc library in cnjunctin with a clinical database, tissue bank and genme-wide assciatin study (GWAS) wuld be mst useful. Third, further develpment f efficient and standardised in vitr ipsc differentiatin prtcls int many mre cell types is essential fr prgress in the field. Frth, cntinuus effrt t recapitulate phentypes f late-nset diseases in vitr, at least partly, wuld be critical t extend their applicatins. Lastly, reducing cmplexity f culture methds will be imprtant t make the system mre easily applicable t high thrughput screening (cited frm [5]). Several effrts are nging wrldwide t address these matters, but still in a highly fragmented way. In Eurpe, the prject EBiSC ( funded by the Innvative Medicines Initiative Jint Undertaking has demnstrated the feasibility and challenges f crdinating existing rganisatinal capacities acrss Eurpe t fast track the establishment f a centralised netwrk and facilities t access a standardised resurce f established hipsc lines and data. EBiSC has established a unique Eurpean based ipsc repsitry and has delivered harmnised and publically accessible Standard Operatins Prcedures (SOPs) fr tissue prcurement, bi-sample tracking, ipsc expansin, crypreservatin, qualificatin and distributin t the research cmmunity. These were implemented t create a quality managed fundatinal cllectin f lines and assciated data made available fr distributin [6]. The critical challenge addressed by this tpic is t build n these imprtant infrastructure, capabilities and knwledge t create a fully sustainable Eurpean hipscs distributin platfrm with wrldwide reach. Need and pprtunity fr public-private cllabrative research The cmplexity f setting up the lgistics and infrastructure t secure cntinued husing, supprt, and distributin f an ipsc cllectin in general, and t secure availability f ipsc assets established within public private partnerships including EBiSC plus assciated infrmatin, needs t be addressed by a public-privatepartnership invlving a variety f stakehlders as it cannt be accmplished by an individual research grup r cmpany and will require a strng cllabrative effrt t be successful. Only a cllabrative endeavur bringing tgether academic labratries and Small- and Medium-sized Enterprise (SMEs) with access t and wnership f necessary hipsc lines, technlgies and lgistics and EFPIA partners that clsely interact with the hipsc banking entity, advising and supprting the further expansin f the hipsc repsitry will ensure that therapeutically relevant areas will cntinue t be addressed and that cnsistency and quality f preparatins meet the needs f drug develpment campaigns. EFPIA will prvide critical feedback n quality and differentiatin ptentials f ipsc lines and precursr cells prvided by the bank facility. Infrmatin and data btained frm certain ipsc lines will be added t the banking entity s infrmatin management t disseminate knwledge n disease understanding and facilitate develpment f screening mdels t be used in drug develpment. This engagement f EFPIA will uniquely enable t capitalise n existing capabilities and knwledge t reach the ultimate gal f self-sustainability f the hipsc banking entity. Scpe A Eurpean ipsc repsitry that perates n a nn-fr-prfit basis and allws researchers access t a cntinuusly expanding number f well characterised and fully QC d ipsc lines with clarified access infrmatin is mandatry t fuel basic research and develpment and drug develpment campaigns. Althugh previus activities have prepared the grund fr such a banking entity, significant aspects listed belw remain t be addressed. The verall bjective f the actin generated frm this tpic is therefre t establish a fully self-sustainable Eurpean human ipsc banking facility, that has t be peratinal within the first three mnths f the actin by seamlessly building n and incrprating existing cell lines, knwledge and infrastructure established within Page 2

3 frmer Eurpean wide initiatives (e.g. EBiSC). The bank has t be able frm the start t handle and deliver a minimum f apprximately 500 quality-cntrlled, disease-relevant (in particular fr neurdegeneratin, Alzheimer s disease and ther taupathies, Parkinsn s disease), cardivascular disease, safety, and diabetes), research-grade ipsc lines, with integrated data and cell services which will be further built n as part f the research and technlgy wrk f the actin. The ultimate gal is t transfrm significant preexisting Eurpean banking infrastructures int a sustainable resurce fr Eurpean research and develpment. The applicant cnsrtium at stage 2 will have t dcument in the full prpsal that this can be achieved efficiently and in the expected timelines as a first g/n g milestne. Thus the fllwing has t be accmplished: Transfer f assets established in previus large standardised Eurpean cllectins with linked data and SOPs t the new bank where apprpriate technlgy is in place t handle cells and guarantee seamless cntinuatin f banking and distributin peratins; Secure cntinued husing, expansin and QC f the existing ipsc cllectin generated in in such previus initiatives; Ensure a cntinued and efficient distributin infrastructure with a Eurpean and wrldwide reach within the first half year after start f the funding perid; Prvide lng-term strage capacity fr up t 10,000 ipsc-vials with a minimum f 3 replicates each under liquid nitrgen gas phase and autmated handling. Capability fr lng-term strage f bisamples; Banking entity and mirrr bank certified t perate accrding t ISO 9001 standards; Secure and further ptimise established QC-prcedures and SOPs by incrprating newly established and accepted methdlgies that becme available during this undertaking; Ensure a cntinued Infrmatin Management System t mnitr the ipsc line status and keep track f ipsc line data, cmplement available infrmatin related t existing lines (e.g. mutatin cnfirmatin and exme sequencing), and incrprate relevant infrmatin including clinical recrds t new entries; Develp the technlgy and establish efficient and reprducible prtcls fr parallelised prductin f bulk quantities f ipscs and/r precursr cells in respnse t drug develpers r future cstumer demands. Within the prject, the cells will be subject t analysis at the participating EFPIA cmpanies in rder t establish disease mdels and screening assays; Further expand the repsitry by incrprating additinal ipsc lines (patient-derived and gene-edited) that: will be established by the cnsrtium during the life time f the actin. It is expected the cnsrtium t supprt cell line cmmissining prjects including gene editing technlgies, like the Crispr/Cassystem, that are requested by the cnsrtium (public and industry partners) as well as relevant members f the external research cmmunity t fuel the repsitry with ipsc lines relevant fr research f benefit t patients and cmmunity. Such requests will be reviewed by the cnsrtium bard cnsisting f the EFPIA-grup and the public partners and apprved, shuld the deliverables cnsidered as f relevance fr the scientific cmmunity and pharmaceutical industry; will becme available in ther publicly funded cnsrtia with a fcus n ipsc technlgy. It is expected the cnsrtium t actively reach ut t ther cell line wners r publicly funded cnsrtia in the prcess f establishing ipsc lines t discuss and secure integratin f new lines int the repsitry. In additin, reaching ut t ther bibanking entities t cmplement ffering t the scientific cmmunity and/r avid duplicatin f wrk is encuraged; are already available in the scientific cmmunity. Ensure ethical and legal matters are in place fr incrpratin f ipsc lines int a public accessible bank t allw freedm t perate fr research and develpment purpses; Establish clinical netwrks that allw the access t well described patient bisamples fr the establishment f ipsc lines and where the ethical and legal grund is established t allw fast access t samples relevant fr academic and industrial research; Page 3

4 Implement all necessary activities t ensure that by the end f the actin the repsitry is fully selfsustainable. Expected key deliverables The key verall deliverable f the actin is the establishment f a self-sustainable ipsc banking facility that fully leverages significant pre-existing infrastructures and knw-hw. Key deliverables and gals are: Establish within the first three mnths f the actin f an Eurpean standardised and at scale human ipsc banking facility by successful transfer f existing ipsc lines, knwledge and infrastructure established within relevant pre-existing Eurpean wide banking (e.g.ebisc) initiatives t this cllabratin; Establish and maintain f a cell line husing facility with a capacity matching the need t handle existing lines and t be extendable t incrprate new nes; Establish and maintain a mirrr cell line bank at capacity; Apply and cntinuusly imprv SOPs t achieve highest standards in ipsc technlgy. QC criteria will be defined fr characterizatin f newly established, expanded, and differentiated ipsc lines; Establish and maintain a Eurpean and wrldwide distributin infrastructure; Thrughut the runtime f the prject the cnsrtium is expected t strive fr self-sustainability f the ipsc repsitry. Therefre, applicants need t frmulate in their prpsals, deliverables, and milestnes related t a business plan that details the peratins after the funding perid. The repsitry will have t be fully self-sustainable by the end f the actin; Ensure a cntinued ipsc line Labratry Infrmatin Management System; Establish efficient and reprducible prtcls/sops t prduce bulk quantities f precursr cells that can be differentiated int cells frm all three germ layers; Further expand the repsitry by incrprating additinal ipsc lines: reach ut t gvernmental funding bdies and the scientific cmmunity t discuss and secure integratin f new ipsc lines int the repsitry; t supprt the cell line cmmissining prjects requested and partially funded by the EFPIA grup r the scientific cmmunity; establish clinical netwrks that will facilitate the establishment f ipsc lines frm well described patients f relevance t the EFPIA partners and the scientific cmmunity; reach ut t and netwrk with ther bibanking entities t capitalize n synergisms. Supprt the ipsc banking entity with regard t ethical and legal aspects t secure freedm t perate and unlimited use in research and develpmental prcesses is attached t ipsc lines. It is expected that applicants address all the abve bjectives in the Shrt prpsal (within the available duratin and budget) and demnstrate a relevant strategy fr achieving them, thrugh partnership with the industry cnsrtium. Expected impact ipsc research and banking cntinues t be fragmented acrss a brad spectrum f institutins in Eurpe, and lacks sufficient scale t supprt the current and anticipated demands f academic and industrial research and develpment. In Eurpe the IMI JU prject EBiSC 1 has prepared the grund fr establishment f a self- 1 Page 4

5 sustaining banking entity by creating an QC ed ipsc repsitry f currently several hundreds f ipsc lines with ethical and legal standards in place. These lines represent imprtant disease areas amng them neurdegenerative diseases (Alzheimer s disease, ther taupathies like frnttempral dementia, and Parkinsn s disease), diabetes, neurpathic pain, and cardivascular diseases that the participating drug develpers are actively researching t prvide nvel treatments t patients. Availability f ipsc lines derived frm patients, as well as f a brad spectrum f lines frm healthy dnrs f different ages, standardised accrding t hw they were made and their in vitr behaviur, and the pssibility f linking a gene cde t cell line phentype reflective f the disease, will enable the research cmmunity t refine riginal clinical diagnsis int ne based n disease stratificatin and thereby design mre precise experiments t discver nvel pathgenic pathways, drug targets and new medicines. This is expected t significantly advance research and develpment activities acrss Eurpe by accelerating the prgress t understanding a certain disease aetilgy as well as finding ptential cures thereby strengthening Eurpean cmpetitiveness. This Eurpean ipsc repsitry will be uniquely psitined t serve as the central Eurpean ipsc repsitry hub t accelerate and facilitate Eurpean research and develpment activities. Therefre, the cnsrtium will have t cntinuusly mnitr the sale f cells prduced by the banking entity, and its trend in rder t develp in the runtime f the prject a plan as t hw t transfrm the repsitry int a self-sustainable business. Ultimately this will secure that the public and private investment will establish a resurce that beynd the runtime f the prject cntinues t supprt and fuel Eurpean basic research as well as drug develpment campaigns in Pharma cmpanies. Ptential synergies with existing Cnsrtia Applicants shuld take int cnsideratin, while preparing their shrt prpsal, relevant natinal, Eurpean (bth research prjects as well as research infrastructure initiatives), and nn-eurpean initiatives. Synergies and cmplementarities shuld be cnsidered in rder t incrprate past achievements, available data and lessns learnt where pssible, thus aviding unnecessary verlap and duplicatin f effrts and funding. Mre specifically, the applicants have t demnstrate awareness f the mst current ipsc landscape acrss Eurpe, t be able t reach ut t relevant prgrams t be incrprated r supprted in rder t ensure that the new banking initiative fully leverages previus significant public and private investments and infrastructures. In Eurpe, a unique repsitry f hipscells has been created by the IMI JU EBiSC prject ( Als, the IMI StemBANCC cllectin f ipsc lines has becme part f the repsitry during the lifetime f the previus IMI EBiSC prject. Other examples f IMI research cllabratins with a strng ipsc fcus are IMI ADAPTED ( IMI PHAGO ( r IMI IMPRiND ( Additinal actins related t r emplying ipsc technlgy will be created in respnse t the tpic launched in the IMI2 12 th Call fr prpsals. Other Eurpean wide r natinal initiatives are : the Human Induced Pluriptent Stem Cell Initiative ( the Human Pluriptent Stem Cell Registry ( natinal initiatives such as El Banc de Líneas Celulares de Barcelna ( the UK Stem Cell Bank ( amngst thers. Furthermre, it will be mandatry fr the applicants t mnitr cllabrative activities acrss the Eurpean R&D landscape t make available the infrastructure t gvernmentally funded scientific prjects in the ipsc area. Industry cnsrtium Page 5

6 The industry cnsrtium will cntribute the fllwing expertise and assets: Facilitatin f transfer f capabilities and knwledge frm EBiSC t reach the ultimate gal f selfsustainability f the ipsc banking entity; Test f the cnsistency and quality f ipsc lines as well as preparatins f bulk quantities f precursr cell preparatins; Interactin t ensure banking f ipsc lines which will aid in disease understanding and develpment f screening mdels t be used in R&D; Establishment f rbust and reliable ipsc disease mdels and screening assays demnstrating prf f cncept fr the use f ipscs fr disease and pharmaceutical research; Supprt fr research activities fcusing n: differentiating and analysing ipsc derived neurns. This will include effrts t shrten the time t achieve electrphysilgically mature neurns with the gal t replace rdent, primary neurn preparatins. A fcus will be n the analysis f ipsc lines derived frm patients suffering frm neurdegenerative diseases r gene-edited t carry certain risk genes r mutatins that are linked t neurdegeneratin. prducing ipsc derived cardimycytes and analysing effects f e.g. pr-arrhythmgenic mutatins r pharmaclgical treatments n the electrphysilgical characteristics f cells. prducing and analysing ipsc derived pancreatic cells t study the underlying mechanisms f diabetes and beta cell dysfunctin. They will further supprt the adaptatin f the ipsc technlgy t autmated screening technlgy by emplying precursr cells prvided by the cnsrtium. Indicative duratin f the actin The indicative duratin f the actin is 36 mnths. Applicant cnsrtium The applicant cnsrtium will be selected n the basis f the submitted shrt prpsals. The applicant cnsrtium, which shuld include SMEs with relevant expertise and experience in ipsc line derivatin and QC, is expected t address all the research bjectives and make key cntributins t the defined deliverables in synergy with the industry cnsrtium which will jin the selected applicant cnsrtium in preparatin f the full prpsal fr stage 2. Significant experience, knwledge and knw-hw in lgistics and infrastructure t perate a Eurpean-wide cell line repsitry including a mirrr ipsc bank accrding t ISO 9001 standards are prerequisites. In additin, this may require mbilising, as apprpriate, the fllwing expertise n: Strage and distributin f cells; The prcurement f bisamples fr ipsc generatin; Lng term strage f bisamples t build aclinically relevant surce f primary material and allw rederivatin f ipsc lines; Reprgramming f human derived cells using state-t-the-art technlgies; Gene-editing appraches t generate isgenic pairs f ipsc cells; Cmprehensive QC f established ipsc lines; Knwledge in lng term strage f bisamples; Knwledge in reprgramming f smatic cells t generate pluriptent stem cells; Page 6

7 State f the art gene editing technlgy (Crispr/Cas); Handling, expansin and QC f ipsc lines; Technlgy and knw-hw t handle large-scale ipsc cultures as well as the ability t prduce bulk quantities f precursr cells r cells with a mature phentype fr distributin; Database management t mnitr status f cell bank and maintain and amend infrmatin available t each cell line; Knwledge in establishing and maintaining nline prtal fr purchasing ipsc lines; Experience in ethical and legal affairs related t the derivatin and use f ipsc; Business r ecnmics experience t transfrm the ipsc repsitry int a self-sustainable business; Scientific / industrial expertise t guide the expansin f the ipsc repsitry in therapeutically relevant disease areas; General prject management (ability t cnsistently set and achieve milestnes n time and within budget; managing varying interests f multiple stakehlders) and prfessinal cmmunicatin expertise (expertise in cmmunicatin tls and systems fr prject management purpses). It may als require mbilising, as apprpriate, the fllwing resurces: A pre-existing Eurpean-wide quality cntrlled fundatinal cllectin f ips cell lines representing specific disease backgrunds with a fcus n neurdegeneratin (Alzheimer s disease and related taupathies, Parkinsn s disease), diabetes and cardivascular diseases and healthy cntrls including assciated data made available fr distributin; IT capabilities t maintain and supprt the labratry infrastructure management system that hsts ipsc related infrmatin and t make accessible the catalgue and the assciated data via the internet; Capacities t allw nline rdering and payment f ipsc lines; Supprt n legal and ethical matters; Cmmercial / industrial applicatin f ipsc derived assets generated within such a cnsrtium including large-scale prductin f ipscs r cell derivatives fr medium-/high- thrughput screenings; Access t lgistics and infrastructure t perate a cell line repsitry including a mirrr ipsc bank; A fully autmated strage system allwing handling f cell lines in the gas phase f liquid nitrgen fr lng term strage purpses; An established distributin pipeline t deliver cell lines t custmers and being peratinal at the utset f the actin. Suggested architecture f the full prpsal The applicant cnsrtium shuld submit a shrt prpsal which includes their suggestins fr creating a full prpsal architecture, taking int cnsideratin the industry cntributins and expertise prvided belw. The final architecture f the full prpsal will be defined by the participants in cmpliance with the IMI2 JU rules and with a view t the achievement f the prject bjectives. In the spirit f the partnership, and t reflect hw IMI2 JU call tpics are built n identified scientific pririties agreed tgether with EFPIA beneficiaries/large industrial beneficiaries, these beneficiaries intend t significantly cntribute t the prgramme and prject leadership as well as prject financial management. The final architecture f the full prpsal will be defined by the participants in cmpliance with the IMI2 JU rules and with a view t the achievement f the prject bjectives. The allcatin f a leading rle within the cnsrtium will be discussed in the curse f the drafting f the full prpsal t be submitted at stage 2. T facilitate the frmatin f the final cnsrtium, until the rles are frmally appinted thrugh the cnsrtium agreement, the prpsed prject leader frm amng EFPIA beneficiaries/large industrial beneficiaries shall Page 7

8 facilitate an efficient negtiatin f prject cntent and required agreements. All beneficiaries are encuraged t discuss the prject architecture and gvernance and the weighting f respnsibilities and pririties therein. The belw architecture fr the full prpsal is a suggestin; different innvative prject designs are welcme, if prperly justified. In summary, the wrk plan shuld enable activities aiming at: managing the existing ipsc cllectin including strage, QC, banking, expansin, and distributin f cell lines; further expanding the ipsc cllectin by prviding technlgy t derive and establish ipsc lines, reaching ut t the Eurpean scientific cmmunity and cnsrtia being peratinal r in the prcess f becming peratinal t make use f synergisms and supprt lgistics necessary t secure cntinued access t ipsc related assets generated within these cnsrtia; cntinuus refinement and ptimisatin f prtcls, QC criteria, and SOPs supprting the peratin f the banking activities; prvide gene editing capabilities t generate ipsc with specific relevant mutatins and creatin f reprter cell lines; develp the technlgy and establish efficient and reprducible prtcls t prduce bulk quantities f ipsc, precursr cells r cells with a mature phentype t fuel industrial screening campaigns. Definitin f QC criteria t deliver cnsistent quality f expanded r differentiated ipsc. The call tpic specifically aims t achieve sustainability as well as a further develpment and maturatin f a Eurpean based ipsc repsitry that includes assets that have been develped by previus private public ipsc cllabratins. One f the key utcmes f this actin will be t build n existing assets, and in the runtime f this prject utline a business plan that will allw the future Eurpean ipsc Banking Entity t cntinue peratins beynd the runtime f the prject t supprt the Eurpean research & develpment activities. The scientific challenges that will be addressed in the actin t be generated by this tpic will further add technlgy, differentiatin prtcls, and ipsc lines including data attached t individual lines t increase the value f the repsitry The bank has t be self-sustainable by end f the actin. Wrk package 1 Prject management: Grant administratin; Cmmunicatin (within the cnsrtium and with relevant external cllabratrs); Disseminatin f scientific results and research data; Sustainability plan facilitating cntinuatin beynd the duratin f the actin; Industry cntributin: c-leadership. Expected Applicant cnsrtium cntributin: All f the abve. Preparatin f business plan t run ipsc banking peratins in a self-sustainable fashin after funding perid t achieve sustainability and cntinue t serve the Eurpean research cmmunity with access t ipsc technlgy. Wrk package 2: Cntinuatin, expansin, and further ptimizatin f banking peratins. This includes Eurpean and wrldwide reach f sales t reach self-sustainability; Page 8

9 Incrpratin f ispc assets develped in previus public private partnerships; Refinement f existing SOPs fr QC f cell lines; Facilitate integratin f apprpriate new ipsc lines generated in ther scientific prjects (IMI2 JU as well as nn-imi2 JU prjects); Establishing cnnectin t clinical netwrk, bibanks, and ther ipsc banking entities, allwing timely access t patient/dnr fibrblast attached t full dnr cnsent, free distributin fr research and develpment, and freedm t perate; Industry cntributin: supprting abve activities. Supprting ipsc line establishment by advising which cell lines are f interest; Expected Applicant cnsrtium cntributin: banking peratins as utlined abve. Wrk package 3: Establishment fr bulk prductin capabilities / SOPs fr generating ipsc r precursr cells t fuel screening campaigns; Definitin QC criteria fr expanded and differentiated ipsc; Industry cntributin: Advice and identificatin f cell lines t be subjected t bulk prductin; Expected Applicant cnsrtium cntributin: Develpment f prtcls fr bulk prductin f ipsc lines and precursr cell lines fr all three germ layers; Adaptatin f differentiatin and maintenance prtcls. Wrk package 4: Prf f cncept experiments acrss industry cnsrtium partners using cell lines prduced in wrk packages 2 and 3 and fcusing n fllwing areas Neursciences: Explre accelerated maturatin and/r aging in ipsc derived neurns with electrphysilgical relevant read uts (multi electrde assays r patch clamp analysis). C-cultivatin with astrcytes and / r micrglia t explre effect f clinical relevant mutatins (Alzheimer s disease, Parkinsn s disease) n neurnal functin. Establish brain rganid cultures suitable fr high cntent imaging analysis. Establish in vitr r xengraft mdels fr pathlgy seeding relating t Alzheimer s disease r Parkinsn s disease. Diabetes Explre technlgies t supprt the adaptatin f established prtcls fr large-scale prductin. Mlecular and functinal analysis f pancreatic prgenitrs as well as mature pancreatic cells. Cardivascular Diseases Page 9

10 Establish standardised differentiatin and maturatin prtcls fr derivatin f cardivascular, ipsc-derived cells (including cardimycytes, endthelial cells, smth muscle cells etc.). Establish functinal assays and readuts t analyse cmpund/drug efficacy in ipsc-derived cardivascular cells; harmnise readuts with FDA-apprved activities (e.g. in CiPA). Assess ability f ipsc-derived cardivascular cells fr patient stratificatin (drug efficacy depending n cmmn genetic variatin). Analyse prtemics/metablmics in ipsc-derived CV cells. Gene editing using e.g. Crispr/Cas system t establish disease relevant ipsc lines; Reprgramming f patient derived smatic cells using state f the art technlgies (nnintegrating technlgies) Industry cntributin: Supprt in differentiating and analysing ipsc derived neurns. This will include effrts t shrten the time t achieve electrphysilgically mature neurns with the gal t replace rdent, primary neurn preparatins. A fcus will be n the analysis f ipsc lines derived frm patients suffering frm neurdegenerative diseases r gene-edited t carry certain risk genes r mutatins that are linked t neurdegeneratin; Supprt in prducing ipsc derived cardivascular cells and analysing effects f e.g. arrhythmgenic mutatins r pharmaclgical treatments n the (electrphysilgical) characteristics f cells; Supprt in differentiating and analysing ipsc derived pancreatic cells t study the underlying mechanisms f diabetes. This includes mlecular as well as functinal assays. Fcus will be n establishing largescale cell culture capabilities as well as cmpetences in gene editing in cllabratin with the relevant partners; The industry grup will further supprt the adaptatin f the ipsc technlgy t autmated screening technlgy by emplying precursr cells prvided by the cnsrtium. Expected Applicant cnsrtium cntributin: Already established and QC ed hipscell lines fr all the abve disease areas; supprt f industry cnsrtium activities by prducing ips-cells and / r precursr cells at quantity t allw screening and ther R&D activities. Knwledge and capabilities in gene-editing and reprgramming f smatic cells t derive ipsc. Reference [1] Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tmda K, Yamanaka S. Inductin f pluriptent stem cells frm adult human fibrblasts by defined factrs. Cell. 2007;131(5): [2] Lu X, Zha T. Clinical therapy using ipscs: hpes and challenges. Genmics Prtemics Biinfrmatics Oct;11(5): di: /j.gpb Epub 2013 Sep 21. [3] Phillips BW and Crk JM. Pluriptent human stem cells: A nvel tl in drug discvery. BiDrugs Apr 1;24(2): [4] McKernan R, Watt FM. What is the pint f large-scale cllectins f human induced pluriptent stem cells? Nat Bitechnl Oct;31(10): [5] Hankwski KE, Hamazaki T, Umezawa A, Terada N. Induced pluriptent stem cells as a next-generatin bimedical interface. Lab Invest Jul;91(7): [6] De Susa PA, Stee R, Wachter E, Bruce K, King J, Heve M et al. Rapid establishment f the Eurpean Bank fr induced Pluriptent Stem Cells (EBiSC) - the Ht Start experience. Stem Cell Res Apr;20: Page 10