SERCA2a Gene Therapy Can Improve Symptomatic Heart Failure in δ-Sarcoglycan-Deficient Animals

Abstract

The loss of dystrophin or its associated proteins results in the development of muscle wasting frequently associated with cardiomyopathy. Contractile cardiac tissue is injured and replaced by fibrous tissue or fatty infiltrates, leading to a progressive decrease of the contractile force and finally to end-stage heart failure. At the time symptoms appear, restoration of a functional allele of the causative gene might not be sufficient to prevent disease progression. Alterations in Ca 2 + transport and intracellular calcium levels have been implicated in many types of pathological processes, especially in heart disease. On the basis of a gene transfer strategy, we analyzed the therapeutic efficacy of primary gene correction in a d-sarcoglycan (d-SG)-deficient animal model versus gene transfer of the Ca 2 + pump hSERCA2a (human sarco-endoplasmic reticulum calcium ATPase 2a), at a symptomatic stage of heart disease. Our results strongly suggest that restoration of d-SG at this stage of disease will not lead to improved clinical outcome. However, restoration of proper Ca 2 + handling by means of amplifying SERCA2a expression in the myocardium can lead to functional improvement. Abnormalities in Ca 2 + handling play an important role in disease progression toward heart failure, and increased SERCA2a levels appear to significantly improve cardiac contraction and relaxation. Beneficial effects persist at least over a period of 6 months, and the evolution of cardiac functional parameters paralleled those of normal controls. Furthermore, we demonstrate that a plasmid formulation based on amphiphilic block copolymers can provide a safe and efficient platform for myocardial gene therapies. The use of synthetic formulations for myocardial gene transfer might thus overcome one of the major hurdles linked to viral vectors, that is, repeat administrations.

Velvet Antler Ameliorates Cardiac Function by Restoring Sarcoplasmic Reticulum Ca2+-ATPase Activity in Rats With Heart Failure After Myocardial Infarction

“…This is consistent with the results of previous study (Zarain-Herzberg et al, 2012) that suggested that decreased SERCA2a activity may have a direct relationship with cardiac dysfunction and cardiomyocyte enlargement (Fernandes et al, 2015). Consequently, SERCA2a is now regarded as a novel gene target for HF therapy in the clinic (Bouyon et al, 2014;Chen et al, 2019). Surprisingly, VA treatment could significantly restore SERCA2a mRNA and protein expression levels, thereby also restoring SERCA2a activity and expression.…”

Gene Therapy for Cardiomyopathies

“…SERCA2a holds a key role in the development and progression of heart failure, so after the initial work by Schwartz and coworkers, it was rather obvious to test its therapeutic potential [38][39][40]. Briefly, we could demonstrate that from a therapeutic perspective at a clinical stage of patent heart failure, great benefits could be obtained by targeting cardiomyocyte Ca 2+ homeostasis through SERCA2a gene expression than rescuing the initial causative genetic defect [41]. These findings as well as results from several other labs strongly support the strategy of cardiac gene therapy for heart failure based on restoring appropriate Ca 2+ handling [42][43][44].…”

Duchenne muscular dystrophy gene therapy in the canine model

“…112,116 AAV-mediated SERCA expression has also improved cardiac function in various canine models of heart failure. 117,118 Based on these results, it is possible that AAV SERCA therapy may also reduce muscle disease in cDMD dogs.…”