Johns Hopkins scientists have successfully used a virus to supply a missing gene and its enzyme product to muscle cells in animals and humans for an extended period. The achievement could have implications in the treatment of an inherited fatal heart disease in children called Pompe's disease.
The two Hopkins-led studies are the first to demonstrate long-term production of the normal enzyme without toxicity and therefore the possibility of single treatment by this method. Results will be presented at 9:30 a.m. and 10 a.m., Nov. 11 at the American Heart Association's 69th annual Scientific Sessions in New Orleans.
Pompe's disease, which causes cardiomyopathy (an enlargement and weakening of heart muscle) in infants, is caused by an inherited metabolic disorder. Heart muscle dysfunction results from a missing or defective enzyme (proteins that stimulate chemical reactions in living tissue) caused by a gene mutation.
Hopkins scientists isolated the defective gene in Pompe's disease and, with Avigen, Inc., researchers, used a harmless virus as a vehicle to carry the normal gene's DNA into mice and into human muscle cells in laboratory dishes. The cells came from children who died of Pompe's disease.
Once inserted into the abnormal cells, the healthy gene material replaced the missing enzyme and restored normal enzyme function over a prolonged period.
"In principle, we know a single gene disorder could be treated by replacing a defective gene," says Paul D. Kessler, M.D., senior author and an assistant professor of medicine at Hopkins. "But the problem has always been a lack of good vectors for getting the normal gene into cells long term."
The Hopkins group used an adeno-associated virus to deliver the gene for the enzyme acid alpha-glucosidase. Healthy DNA was injected into muscles in the mice and began producing the enzyme two weeks later and continued to produce it for at least three months. Further animal studies are planned.
"These results demonstrate that adeno-associated viral vectors can effectively transfer genes into muscles in animals and lead to sustained expression of a therapeutic protein," says Barry J. Byrne, M.D., Ph.D., lead author and an assistant professor of pediatric cardiology at Hopkins.
Gene therapy involves treating diseases by delivering genes into cells to restore normal cell actions or to stop abnormal cell actions. The genes are delivered by vectors, harmless viruses that enter the target cell, delivering the gene with them.
The studies were supported by the Peter Belfer Laboratories for Myocardial Research at Hopkins, the American Heart Association's Delaware branch, the March of Dimes Birth Defects Foundation and the W.W. Smith Foundation.