The loss of dystrophin or its associated proteins results in the development of muscle wasting frequently associated with a cardiomyopathy. Contractile cardiac tissue is injured and replaced by fibrous tissue or fatty infiltrates, leading to 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 Ca2+ transport and intracellular calcium levels have been implicated in many types of pathological processes, especially in heart disease. Based on a gene transfer strategy, the authors analyzed the therapeutic efficacy of primary gene correction in a delta-sarcoglycan (δ-SG) deficient animal model versus gene transfer of the Ca2+ pump hSERCA2a, at a symptomatic stage of heart disease. Their results strongly suggest that restoration of δ-SG at this stage of disease will not lead to improved clinical outcome. However, restoration of proper Ca2+ handling by means of amplifying SERCA2a expression in the myocardium can lead to functional improvement. Abnormalities in Ca2+ handling play an important role in disease progression towards heart failure and increased SERCA2a levels appear to significantly improve cardiac contraction and relaxation. Beneficial effects persist at least over a period of six months and the evolution of cardiac functional parameters paralleled those of normal controls. Furthermore, it was demonstrated that 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, repeat administrations.
