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

Abstract

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.

Creation of an iPSC-Based Skeletal Muscle Model of McArdle Disease Harbouring the Mutation c.2392T>C (p.Trp798Arg) in the PYGM Gene

“…Recently, in our laboratory, we obtained, for the first time, a human skeletal muscle model of McArdle disease, based on the use of iPSC technology. This model harbours the most frequent pathogenic variant in the Caucasian population in the PYGM gene, NM_005609.4: c.148C>T (p.Arg50Ter) [ 8 ]. Here, we present the generation of a human iPSC-based skeletal muscle model of McArdle disease carrying the second most frequent pathogenic variant in the Spanish population in the PYGM gene, NM_005609.4: c.2392T>C (p.Trp798Arg).…”

“…Recently, our group reported the generation of the first human in vitro skeletal muscle model of McArdle disease based on iPSC technology [ 8 ]. This model was obtained from a patient harbouring the most common genetic defect in the PYGM gene described in the Caucasian population: NM_005609.4: c.148C>T (p.Arg50Ter).…”

Advanced Cellular Models for Rare Disease Study: Exploring Neural, Muscle and Skeletal Organoids

“…McArdle disease [146], carnitine palmitoyltransferase II (CPT II) deficiency [147] and nemaline myopathy [148], allowing for a good replication of the main disease-related pathological features.…”

Pharmaceuticals Promoting Premature Termination Codon Readthrough: Progress in Development

“…RTC14 increased mRNA expression of the XPC gene and NAGLU gene in fibroblasts from xeroderma pigmentosum group C and Sanfilippo C patients, respectively [ 160 ]. However, RTC13 or RTC14 could not suppress PTCs associated with hemophilia A, McArdle disease, chronic granulomatous disease, and Wiscott-Aldrich syndrome [ 159 , 161 , 162 , 163 ]. A study of the SAR of RTC13 revealed that several derivatives containing variations on both aryl and thiazolidinone rings exhibited good readthrough activity.…”