Problems and potential for gene therapy in Duchenne muscular dystrophy.

Hopes ran high that a cure for Duchenne muscular dystrophy (DMD) would quickly follow the discovery of dystrophin by Lou Kunkel and his group in the 1980's. Myoblast transplantation, the favoured method of gene 'complementation', unfortunately did not progress beyond the experimental stage. A more sober approach to gene therapy followed using a variety of transfection or direct methods to introduce the normal gene. In view of these advances it is timely for the potential of gene therapy for DMD to be considered in the light of the disease process. It may be assumed that if dystrophin is replaced muscle fibre necrosis will cease. For this purpose expression of the gene should be continuous and expressed throughout the body well before there are irreversible changes. It would seem that gene therapy would not be particularly helpful if this occurs when the muscle lesions are near the end stage. If our objective is to retain ambulation dystrophin must be replaced well before the end stage. It should be kept in mind that even when the disorder first becomes clinically apparent at the age of about 5 years, muscle lesions are very advanced in the limb girdle groups. Therefore, the best that may be hoped to achieve by gene therapy at the age of 5 years would be to arrest the process at that stage of involvement with the patient having permanent but static weakness. Cardiac lesions are probably minimal at this time. To improve life expectancy, the respiratory muscles would need to be preserved. The enormous size of the gene is another difficulty so that some thought has been given to the introduction of a 'minigene' converting the clinical phenotype from DMD to the more benign Becker phenotype with improved life expectancy.