Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w

AAV1.SERCA2a mitigates heart failure in DMD pigs

A. Bähr1, N. Hornaschewitz1, M. Stirm2, P. Hoppmann1, T. Bozoglu1, K.-L. Laugwitz1, N. Klymiuk1, E. Wolf2, R. J. Hajjar3, C. Kupatt1

1Klinik und Poliklinik für Innere Medizin I, Klinikum rechts der Isar der Technischen Universität München, München; 2Lehrstuhl für molekulare Tierzucht und Biotechnologie, LMU München, Oberschleissheim; 3Ring Therapeutics, Cambridge MA, US;

Aims: Treatment of genetic cardiomyopathies is often unsatisfying, since pharmacologic agents do not alter the disease-causing mutation. However, end-stage heart failure, regardless of the etiology, is characterized by improper calcium handling. In this study, we tested whether a normalization of Ca2+-handling by restoration of SERCA2a expression in cardiomyocytes mitigates heart failure and arrhythmogenesis in a porcine model of Duchenne muscular dystrophy (DMD) in pigs.  Methods and results: We generated pigs lacking exon 52 of the DMD gene. Male offspring are characterized by heart failure, arrhythmogenesis due to distinct regions of low or no-amplitude action potentials and by sudden cardiac death before 4 months of age. Germline correction of the loss of function mutation by additional excision of neighbouring exon 51 induced a Becker phenotype (BMD), with normalized cardiac function (EF 42 +/- 6% BMD vs. 34 +/- 2% DMD) and a largely reduced area of no amplitude in electrophysiology mapping. Using a different approach, 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 vs. 34 +/- 2% DMD) but did not alter the amount of no-amplitude areas per LV. Conclusions: Compared to ubiquitous correction of DMD by editing the genome of a donor cell for SCNT, which induced preserved pump function and action potential amplitudes, a moderate dose of AAV1.SERCA2a sufficed to normalize left ventricular function, but did not affect the no amplitude areas. Hence, AAV1.SERCA2a combined with antitachycardic pacemaker protection may serve as treatment option for DMD cardiomyopathy.

https://dgk.org/kongress_programme/jt2023/aP2218.html