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 δ-
sarcoglycan (δ-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 δ-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.