{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T08:26:49Z","timestamp":1793176009299,"version":"4.5.0"},"posted":{"date-parts":[[2025,2,11]]},"group-title":"Neuroscience","reference-count":26,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T00:00:00Z","timestamp":1739232000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Induced pluripotent stem cell (iPSC) models are powerful tools for neurodegenerative disease modelling, as they allow mechanistic studies in a human genetic environment and they can be differentiated into a range of neuronal and non-neuronal cells. However, these models come with inherent challenges due to line-to-line and clonal variability. To combat this issue, the iPSC Neurodegenerative Disease Initiative (iNDI) has generated an iPSC repository using a single clonal reference line, KOLF2.1J, into which disease-causing mutations and revertants are introduced via gene editing. Here we describe the generation and validation of lines carrying the most common causative mutation for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a repeat expansion in the\n                  <jats:italic>C9orf72<\/jats:italic>\n                  gene, for the iNDI collection of neurodegenerative iPSC models. We demonstrate that these\n                  <jats:italic>C9orf72<\/jats:italic>\n                  knock-in lines differentiate efficiently into neurons and display characteristic\n                  <jats:italic>C9orf72<\/jats:italic>\n                  -associated pathologies, including reduced C9orf72 levels and the presence of dipeptide repeat proteins (DPRs) and RNA foci, which increase in abundance over time in culture. These pathologies are not present in revertant cells lacking the repeat expansion. These repeat expansion and revertant cell lines are now available to academic and for-profit institutions through the JAX iPS cell repository and will help to facilitate and standardise iPSC-based ALS\/FTD research.\n                <\/jats:p>","DOI":"10.1101\/2025.02.10.637041","type":"posted-content","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T05:45:25Z","timestamp":1739252725000},"source":"Crossref","is-referenced-by-count":4,"title":["Generation of\n                  <i>C9orf72<\/i>\n                  repeat knock-in iPSC lines for modelling ALS and FTD"],"prefix":"10.64898","author":[{"given":"Rachel","family":"Coneys","sequence":"first","affiliation":[{"name":"UK Dementia Research Institute at UCL, London, UK"},{"name":"Dept of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander J.","family":"Cammack","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at UCL, London, UK"},{"name":"Dept of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Remya R.","family":"Nair","sequence":"additional","affiliation":[{"name":"Mammalian Genetics Unit, MRC Harwell Institute, Oxfordshire, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Thompson","sequence":"additional","affiliation":[{"name":"Mammalian Genetics Unit, MRC Harwell Institute, Oxfordshire, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Mechtersheimer","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at UCL, London, UK"},{"name":"Alzheimer\u2019s Research UK UCL Drug Discovery Institute, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mireia","family":"Carcol\u00e9","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at UCL, London, UK"},{"name":"Dept of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yashica","family":"Gupta","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at UCL, London, UK"},{"name":"Dept of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel E.","family":"Rech","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Flower","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at UCL, London, UK"},{"name":"Dept of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niamh","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at King\u2019s College London, UK"},{"name":"Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King\u2019s College London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc-David","family":"Ruepp","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at King\u2019s College London, UK"},{"name":"Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King\u2019s College London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Mizielinska","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at King\u2019s College London, UK"},{"name":"Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King\u2019s College London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"Ducotterd","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Research UK UCL Drug Discovery Institute, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah J.","family":"Tabrizi","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at UCL, London, UK"},{"name":"Dept of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2850-9936","authenticated-orcid":false,"given":"Elizabeth M.C.","family":"Fisher","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Cunningham","sequence":"additional","affiliation":[{"name":"Mammalian Genetics Unit, MRC Harwell Institute, Oxfordshire, UK"},{"name":"MRC Prion Unit at UCL and UCL Institute for Prion Diseases, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5296-8051","authenticated-orcid":false,"given":"Michael","family":"Ward","sequence":"additional","affiliation":[{"name":"Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William C.","family":"Skarnes","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian M.","family":"Isaacs","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at UCL, London, UK"},{"name":"Dept of 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