Duchenne muscular dystrophy is a devastating muscle disease caused by loss-of-function mutations in the dystrophin (DMD) gene. Since pharmacologic treatment is ineffective over time, gene therapy including gene editing is rapidly evolving. In patients with advanced disease, who suffer from cardiomyopathy, locoregional AAV.SERCA2a gene therapy is a novel treatment option, which we tested in a porcine model of DMD.

We generated pigs lacking exon 52 of the DMD gene. Male offspring are characterized by heart failure (EF33±3%), arrhythmogenesis due to distinct regions of low or no-amplitude action potentials and by sudden cardiac death before 4 months of age. Using intracoronary delivery of AAV1.SERCA2a at a dose of 3x10¹³ virus genomes (vg) per pig by slow antegrade infusion of LAD & LCx improved left ventricular ejection fraction (EF 46±5% +AAV1.SERCA2a), although it didn’t significantly alter the amount of no-amplitude areas per LV.

Notably, the recruitment of CD45+ leukocytes significantly increased in DMD pigs, was reduced to wildtype levels after AAV.Serca2a treatment. Microvascular density was comparable to WT levels as opposed to severely reduced levels in DMD hearts. Finally, principal component analysis of the DMD proteome indicated, that a variety of components were moving towards WT levels, including inflammatory, mitochondrial and sarcomeric proteins.

AAV1.SERCA2a sufficed to normalize left ventricular function in DMD pigs, and initiated partial normalization of structural alterations of DMD hearts (microvessel density, inflammation). We conclude that although SERCA2a gene therapy does not correct the disease-causing mutation, it´s pleiotropic effects on the proteome help to partially rescue the DMD cardiomyopathy.