Gene transfer studies in animals: what do they really tell us about the prospects for gene therapy in DMD?

There is a pressing need to develop new therapeutic approaches to Duchenne muscular dystrophy, an X-linked fatal disease primarily affecting skeletal and cardiac muscle. Gene therapy is an approach that has attracted much interest since the description of the Duchenne muscular dystrophy gene and its mutations in 1987. Since 1990 numerous reporter and dystrophin gene transfer studies have been conducted on muscles of animals but mostly in mice. Experimental protocols have ranged from germ-line gene transfer (via the production of transgenics) to somatic gene transfer studies using viral or non-viral vectors. But what have we actually learned from such studies that can be applied to patients with Duchenne muscular dystrophy? Various dystrophin, utrophin and integrin recombinant cDNAs have been shown to prevent the development of muscular dystrophy in transgenic dystrophic (mdx) mice. Somatic gene transfer prior to the onset of pathology have been shown to prevent the development of the muscular dystrophy in the mdx mouse but the data is less convincing for the beneficial effects of somatic gene transfer following the establishment of pathology. The time of onset and the course of the disease differ substantially between mouse and man and raise concerns about the applicability of gene therapy in man where the disease manifests in utero and the progression is more severe. The other major concern relates to uncertainty over the efficiency of the different vectors in man, particularly as many patients are likely to have encountered the infectious forms of the viruses that are proposed as vectors.