Prospects for gene therapy for inherited cardiomyopathies.

Over the last few years the genes responsible for a number of genetic diseases of the cardiovascular system have been identified. These have included X-linked and autosomal dominant dilated cardiomyopathy, and hypertrophic cardiomyopathy. Genetic heterogeneity has been described in both of these diseases but a commonality of function has been apparent: defects in cytoskeletal proteins cause dilated cardiomyopathy and mutations in sarcomeric proteins cause hypertrophic cardiomyopathy. This led us to develop a 'final common pathway' hypothesis as a framework for selecting candidate genes for mutation screening in families with these diseases. The characterization of gene mutations has led to the development of therapies specifically targeting the defective protein or the pathway in which it is involved. These have included the use of pharmaceutical agents to replace or to antagonize the mutated protein, and replacement of the defective gene with a functional one (gene therapy). While early studies using gene therapy vectors were promising, translating studies in animals to viable therapeutic options for humans has remained problematic. There have been many publications describing the use of vectors to transduce target cells for the correction of gene defects, including recombinant retroviruses, adenoviruses, and adeno-associated viruses, as well as non-viral vectors. In this review we will discuss the identification of gene defects associated with cardiomyopathies, and the potential of gene therapy for the treatment of these diseases, as well as addressing some concerns related to the use of adenovirus-based vectors, a virus known to be an etiologic agent of acquired dilated cardiomyopathy.