Research ArticleGene Therapy

Titin splicing regulates cardiotoxicity associated with calpain 3 gene therapy for limb-girdle muscular dystrophy type 2A

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Science Translational Medicine  27 Nov 2019:
Vol. 11, Issue 520, eaat6072
DOI: 10.1126/scitranslmed.aat6072

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Safety through splicing

Limb-girdle muscular dystrophy type 2A is characterized by progressive muscle weakness resulting from deficiency in calpain 3. Lostal et al. investigated the therapeutic effect of recombinant adeno-associated viral (AAV) vector expressing CAPN3 and a miR-208a target sequence in mice and nonhuman primates. Mice lacking calpain 3 and dysferlin (a severe model of myopathy) showed reduced dystrophy and restoration of calpain 3 expression after AAV treatment. In contrast to previous murine studies, treatment did not cause cardiotoxicity in nonhuman primates, although transgene was expressed in the heart. The authors identified species-specific differences in calpain 3 binding sites on titin between mice, nonhuman primates, and humans, which could account for differences in cardiotoxicity. Results support further investigation into calpain 3 gene therapy as a treatment for limb-girdle muscular dystrophy.

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