Generation of the first human In vitro model for McArdle disease based on iPSC technology
Author
Ortuño-Costela, María del Carmen; Cerrada, Victoria; Moreno-Izquierdo, Ana; García-Consuegra, Inés; Laberthonnière, Camille; Delourme, Mégane; Garesse Alarcón, Rafael; Arenas, Joaquín; Fuster García, Carla; García García, Gema; Millán, José María; Magdinier, Frédérique; Gallardo, María EstherEntity
UAM. Departamento de BioquímicaPublisher
MDPIDate
2022-11-12Citation
10.3390/ijms232213964
International Journal of Molecular Sciences 23.22 (2022): 13964
ISSN
1661-6596 (print); 1422-0067 (online)DOI
10.3390/ijms232213964Funded by
This work has been funded by grants from the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III (ISCIII): PI15/00484, CP16/00046 and PI18/00151 to MEG and PI17/02052 to JA (co-funded by European Regional Development Fund “A way to make Europe”); PI21/00162 and CPII21/00011 co-funded by the European Union to MEG. MdCOC receives grant support from the ‘Ministerio de Educación, Cultura y Deporte’ (FPU16/03895), ‘Fundación para la Investigación Biomédica Hospital 12 de Octubre’ (2022/0065, i+12-AY20220114-1) and EMBO Grant 8917. CL and MD were recipient of a fellowship from the French Ministry of Education. The work in FM’s laboratory was funded by “Association Française contre les Myopathies” (AFM; TRIM-RD and MoThARD) and from the Excellence Initiative of Aix-Marseille University-A*Midex, a French “investissement d’avenir programme” AMX-19-IET-007 through the Marseille Maladies Rares (MarMaRa) Institute (phD fellowship to CL)Project
Gobierno de España. PI15/00484; Gobierno de España. CP16/00046; Gobierno de España. PI17/02052; Gobierno de España. FPU16/03895Editor's Version
https://doi.org/10.3390/ijms232213964Subjects
CRISPR/Cas9; disease modelling; gene editing; iPSCs; isogenic control; McArdle disease; PYGM; read-through drugs; skeletal muscle differentiation; MedicinaRights
© 2022 by the authorsAbstract
McArdle disease is a rare autosomal recessive disorder caused by mutations in the PYGM gene. This gene encodes for the skeletal muscle isoform of glycogen phosphorylase (myophosphorylase), the first enzyme in glycogenolysis. Patients with this disorder are unable to obtain energy from their glycogen stored in skeletal muscle, prompting an exercise intolerance. Currently, there is no treatment for this disease, and the lack of suitable in vitro human models has prevented the search for therapies against it. In this article, we have established the first human iPSC-based model for McArdle disease. For the generation of this model, induced pluripotent stem cells (iPSCs) from a patient with McArdle disease (harbouring the homozygous mutation c.148C>T; p.R50* in the PYGM gene) were differentiated into myogenic cells able to contract spontaneously in the presence of motor neurons and generate calcium transients, a proof of their maturity and functionality. Additionally, an isogenic skeletal muscle model of McArdle disease was created. As a proof-of-concept, we have tested in this model the rescue of PYGM expression by two different read-through compounds (PTC124 and RTC13). The developed model will be very useful as a platform for testing drugs or compounds with potential pharmacological activity
Files in this item
Google Scholar:Ortuño-Costela, María del Carmen
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Cerrada, Victoria
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Moreno-Izquierdo, Ana
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García-Consuegra, Inés
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Laberthonnière, Camille
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Delourme, Mégane
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Garesse Alarcón, Rafael
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Arenas, Joaquín
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Fuster García, Carla
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García García, Gema
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Millán, José María
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Magdinier, Frédérique
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Gallardo, María Esther
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