A new way of delivering corrective genes with a single injection into a vein holds promise for long-lasting treatments of hereditary diseases of the heart, University of Florida researchers report.
UF researchers used the approach to successfully reverse symptoms in mice with a form of muscular dystrophy that damages the heart. They also tested the virus-based delivery method in monkeys and found genes were readily absorbed by heart muscle cells, and the effect persisted for months.
The findings, published in the online edition of Circulation Research, pave the way for studies in humans that could begin as soon as early next year for patients with Pompe disease, a rare form of muscular dystrophy that is usually fatal in the first year of life.
"Nine years ago we knew we could get long-term gene expression in the heart but it was with direct injection into the heart muscle and it was inefficient," said UF pediatric cardiologist Barry J. Byrne, M.D., Ph.D., the paper's senior author and director of the Powell Gene Therapy Center. "The difference here is that we can deliver a much lower dose of the vector into a vein like any other drug, and the corrective gene collects in the heart."
Scientists say gene therapy looks increasingly feasible for the treatment of cardiovascular conditions linked to faulty genes or congenital metabolic diseases, including atherosclerosis, stroke, muscular dystrophy and an enlargement of the heart muscle known as dilated cardiomyopathy.
But efforts to begin testing it in people have been slowed by the need to find ways to deliver corrective genes easily and efficiently, so they go where they are needed. A number of conditions, for example, affect both heart and skeletal muscle and will require the widespread delivery of genes throughout the body, instead of to a localized site, to prevent or correct disease.
"There are many forms of adult heart disease that are now well-understood as having a genetic basis; all of the arrhythmias, problems that are due to a family of diseases called long Q-T syndrome, the heart failure category where many folks have been attempting to modify contractility with gene transfer," said Byrne, who also is affiliated with the UF Genetics Institute. "We're using the very same strategies used with medical treatment but without ongoing use of medications."
In evaluating methods of delivering the genes, UF researchers compared three subtypes of the adeno-associated virus, or AAV, which is not known to cause disease and does not appear to trigger a major immune system reaction. They tested the ability of AAV-1, AAV-8 and AAV-9 to insert genes into skeletal and heart muscle in newborn and in adult mice.
Tests revealed that AAV-9 was taken up throughout the heart muscle at 200 times the levels achieved with AAV-1. In contrast, AAV-8 was taken up by heart muscle at 20 times the levels achieved with AAV-1, though it was less precise, also delivering a significant amount of its genetic payload to the liver and to other muscles.
Because AAV-9 was so readily taken up by cells, a lower dose likely could be used to achieve a therapeutic effect in people, Byrne said. It also has a unique outer shell that helps it break through blood vessel walls so it can be readily taken up by cells requiring repair.
The scientists also modified AAV-9 to contain copies of a therapeutic gene that pumps out an enzyme missing in a mouse model for Pompe disease. The ailment is caused by a single defective gene that fails to produce adequate levels of an enzyme that normally breaks down the carbohydrate glycogen, used to store energy. The disease causes gradual weakening of muscle and heart tissue when glycogen accumulates in muscles, limiting their ability to contract.
"This is a way of delivering gene therapy to the heart that is aimed at treating genetic diseases affecting the heart," Byrne said. "It's efficient and long lasting. One of the other distinguishing features of our research is it's probably the first to demonstrate a physiologic correction of a genetic cardiac abnormality."