McArdle disease : efficacy of gene therapy in the model mouse

McArdle disease is a disorder of carbohydrate metabolism that causes painful skeletal muscle cramps and skeletal muscle damage leading to transient myoglobinuria and increased risk of kidney failure. McArdle disease is caused by recessive mutations in the muscle glycogen phosphorylase gene (PYGM) leading to absence of PYGM enzyme in skeletal muscle and preventing access to energy from muscle glycogen stores. There is currently no cure for McArdle disease.

Using a preclinical animal model, the researchers aimed to identify a clinically translatable and relevant therapy for McArdle disease. They evaluated the safety and efficacy of recombinant adeno-associated virus serotype 8 (rAAV8) to treat a murine model of McArdle disease via delivery of a functional copy of the disease-causing gene, Pygm. Intraperitoneal injection of rAAV8-Pygm at post-natal day 1-3 resulted in Pygm expression at 8 weeks of age, accompanied by improved skeletal muscle architecture, reduced accumulation of glycogen and restoration of voluntary running wheel activity to wild-type levels.

The authors did not observe any adverse reaction to the treatment at 8 weeks post-injection. Thus, they have investigated a highly promising gene therapy for McArdle disease with a clear path to the ovine large animal model endemic to Western Australia, and subsequently to patients.


Systemic AAV8-mediated delivery of a functional copy of muscle glycogen phosphorylase (Pygm) ameliorates disease in a murine model of McArdle disease. McNamara EL, Taylor RL, Clayton JS, Goullee H, Dilworth KL, Pinós T, Brull A, Alexander IE, Lisowski L, Ravenscroft G, Laing NG, Nowak KJ. Hum Mol Genet. 2019 Sep 12. pii: ddz214.