In the course of studying autoimmune mechanisms in myositis, an inflammatory muscle disease, a number of patients with other muscle disease have been evaluated. Two genetic metabolic myopathies, phosphofructokinase (PFK) deficiency and acid maltase (GAA) deficiencies, have been selected for studies at the molecular level. The studies of PFK deficiency, now drawing to a close, have focussed on defining the genetic abnormalities in different patient populations, and a number of mutations have been found. Experiments in collaboration with a laboratory in Germany have used a yeast expression system to study the biochemical properties of the abnormal enzymes. Studies of GAA deficiency have centered on the adult form of the disease. An infantile form is fatal in the first year of life. Studies on the mechanism of a common GAA mutant genotype, shared by 70% of adult-onset patients, have been expanded in a model system. This system enabled us to identify a transcriptional silencer in the GAA gene, which has implications for gene therapy. Experiments to lay the ground work for therapeutic gene transfer with a recombinant retrovirus bearing the normal cDNA resulted in the restoration of GAA activity in affected fibroblasts. Similar experiments with affected myoblasts are ongoing. Plans are underway for developing a GAA deficient mouse model for in vivo gene therapy.
Showing the most recent 10 out of 17 publications
