Generation of the First Human In Vitro Model for McArdle Disease Based on iPSC Technology

María del Carmen Ortuño-Costela (1, 2) , Victoria Cerrada (1) , Ana Moreno-Izquierdo (1) , Inés García-Consuegra (1, 3) , Camille Laberthonnière (4) , Mégane Delourme (4) , Rafael Garesse (2) , Joaquín Arenas (1, 3) , Carla Fuster García (3) , Gema García García (3) , José María Millán (3) , Frédérique Magdinier (4) , María Esther Gallardo (1)

1 Hospital Universitario 12 de Octubre [Madrid]
2 UAM - Universidad Autónoma de Madrid
3 CIBERER - Centro de Investigación Biomédica en Red de Enfermedades Raras
4 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille

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.

Mots clés: CRISPR/Cas9; McArdle disease; PYGM; disease modelling; gene editing; iPSCs; isogenic control; read-through drugs; skeletal muscle differentiation.

Domaines: Génétique; Médecine humaine et pathologie

María del Carmen Ortuño-Costela, Victoria Cerrada, Ana Moreno-Izquierdo, Inés García-Consuegra, Camille Laberthonnière, et al.. Generation of the First Human In Vitro Model for McArdle Disease Based on iPSC Technology. International Journal of Molecular Sciences, 2022, 23 (22), pp.13964. ⟨10.3390/ijms232213964⟩. ⟨hal-04039822⟩