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We are analyzing https://www.biorxiv.org/content/10.1101/2025.06.22.660928v1.

Title:
Advanced human iPSC-based modelling of LMNA-related congenital muscular dystrophy enables development of targeted genetic therapies for muscle laminopathies | bioRxiv
Description:
LMNA -related congenital muscular dystrophy (L-CMD) is amongst the most severe forms of laminopathies, which are diseases caused by pathogenic variants in the LMNA gene. LMNA encodes the proteins LAMINs A and C, which assemble with LAMIN B1 and B2 to form the nuclear lamina: a meshwork providing structural stability to the nucleus that also regulates chromatin organisation and gene expression. Research into L-CMD mechanisms and therapies i hindered by lack of humanised, tissue-specific models that accurately recapitulate disease phenotypes. We previously reported that LMNA -mutant induced pluripotent stem cell (iPSC)-derived skeletal muscle cells have nuclear shape abnormalities and LAMIN A/C protein mislocalisation. Here, we expand the selection of L-CMD patient-derived iPSCs and validate disease-associated readouts using a transgene-free based protocol which more accurately mimics skeletal myogenesis. Results showed no defects in developmental myogenesis, but recapitulation of pathological nuclear shape abnormalities in 2D and 3D cultures, nuclear envelope protein mislocalisation and transcriptomic alterations across multiple pathogenic LMNA variants. We then utilised this platform to assess LMNA gene editing strategies. CRISPR-based exon removal generated stable RNA and protein LAMIN A/C species, without significant normalisation of nuclear morphological phenotypes. Conversely, precise editing of the same mutation showed complete reversal of disease-associated nuclear morphometrics. Our data provide the foundation for a humanised in vitro disease and therapy modelling platform for this complex and severe muscle disorder. ![Figure][1]</img> HIGHLIGHTS ### Competing Interest Statement The authors have declared no competing interest. Muscular Dystrophy UK, 19GRO-PS48-0188-1 European Union, 101080690, 759108 UK Research and Innovation, 10078461, 10080927, 10079726 LifeArc, CMCK-UK.FID119430465 Biotechnology and Biological Sciences Research Council, BB/J014567/1, BB/M009513/1 AFM-Telethon, 29063 Cancer Research UK, https://ror.org/054225q67, CC0199 Medical Research Council, https://ror.org/03x94j517, CC0199 Wellcome Trust, https://ror.org/029chgv08, CC0199 National Institute for Health Research, https://ror.org/0187kwz08 [1]: pending:yes
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Keywords {🔍}

biology, nuclear, research, muscle, lcmd, lmna, lmnamutant, diseaseassociated, medrxiv, subject, reviews, clinical, results, preprint, muscular, dystrophy, therapies, gene, lamin, phenotypes, cell, ipscderived, skeletal, cells, protein, ipscs, myogenesis, cancer, institute, biorxiv, university, trials, epidemiology, search, advanced, modelling, lmnarelated, congenital, genetic, laminopathies, profile, pdf, severe, pathogenic, variants, humanised, accurately, recapitulate, disease, shape,

Topics {✒️}

l-cmd patient-derived ipscs epidemiology subject categories developmental myogenesis clinical trials 19gro-ps48-0188-1 european union targeted genetic therapies transgene-free based protocol bb/m009513/1 afm-telethon health-related information l-cmd mechanisms biorxiv subject category genetics microbiology author/funder epidemiology papers reviews keyword advanced search l-cmd severe muscle disorder download figureopen muscle laminopathies daniel cc0199 national institute nuclear shape abnormalities therapy modelling platform lmna gene cc0199 wellcome trust valentina maria lionello angela clara-hwang regulates chromatin organisation tissue-specific models generous financial support chan zuckerberg initiative imperial college london vrije universiteit amsterdam articles animal behavior nuclear morphological phenotypes lmna encodes context ipsc org/0187kwz08 copyright competing interest show health research 759108 uk research pathogenic variants transgene-free nuclear phenotypes protein mislocalisation precise editing therapies

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