Research team improves safety of LGMD2A gene therapy

Limb-girdle muscular dystrophy type 2A (LGMD2A or LGMDR1) is a neuromuscular disorder hat causes progressive muscle weakness and has no cure. The condition is caused by mutations in the calpain 3 gene (CAPN3). Previous experiments using adeno-associated viral (AAV) vector–mediated calpain 3 gene transfer in mice indicated cardiac toxicity associated with the ectopic expression of the calpain 3 transgene. Now a team at French INSERM (Paris) and Karolinska Institute (Stockholm, Sweden) have created an improved gene therapy that can treat a form of muscular dystrophy in animal models without causing heart damage.

Calpain 3 is present in skeletal muscle and to a lesser extent in the heart. William Lostal and colleagues previously created a gene therapy for LGMD2A, but the treatment was toxic to the heart in mice because it activated calpain 3 in both the heart and skeletal muscles. In the current study, published in Science Translational Medicine, the researchers refined their approach by combining an adeno-associated viral vector expressing CAPN3 with a heart-specific microRNA, which avoids heart toxicity while still correcting LGMD2A in the muscle.

Lostal et al. administered their therapy to a mouse model of muscle breakdown and calpain 3 and dysferlin deficiency and saw that it slowed the breakdown of skeletal muscle and restored the expression of calpain 3. The gene therapy was also well-tolerated when given to healthy macaques and boosted the expression of calpain 3 without causing heart toxicity. Finally, they found that titin – a binding partner of calpain 3 – showed differences in its calpain 3 binding sites across mice, macaques and humans, an observation that could explain the previously-observed heart toxicity. The interest for LGMD2A gene therapies in the market is high.

In May, Sarepta Therapeutics acquired a preclinical LGMD2A gene therapy programme developed by the Research Institute at Nationwide Children’s Hospital in Ohio. The calpain-3 programme uses a rhesus monkey-derived adeno-associated virus (AAVrh74) to directly deliver functional copies of the calpain-3 gene to patients’ skeletal muscle, intending to prevent further muscle damage via calpain-3 waste proteins.