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UF scientists test improved gene therapy method for hereditary heart conditions

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 July 27 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."

Additional tests in rhesus monkeys conducted in conjunction with scientists at the California National Primate Research Center at the University of California at Davis showed that AAV-9 easily passes into the heart muscle in primates after a single intravenous injection, and the effects are long lasting.

"AAV-9 had a particular affinity for heart muscle that AAV-8 didn't," Byrne said. "Right now AAV-9 seems to be our best solution for heart problems.

"The primates were done to give us insight into how this could be used in children," he said, adding that UF researchers hope to launch a trial in patients with Pompe disease early next year. "Many of the inborn errors have their most feared effects early in life, so we're pushing toward being able to do prevent disease as opposed to trying to correct later. We keep trying to get closer and closer to clinical studies that will help patients-that's the real goal."

R. Jude Samulski, Ph.D., director of the Gene Therapy Center at the University of North Carolina-Chapel Hill, said each viral type is "like a FedEx truck that carries a ZIP code that determines where the truck is going to take its payload to."

"Laboratories are engineering new ZIP codes onto these vectors so they can try to control where they go," he said. "Then they become more like a traditional drug that has these properties and only these properties. We're using templates out in Mother Nature as our blueprint. Once we learn these places where they work, then we can strategically control them and use them for our advantage. It's an exciting time in this area.

"I equate it to the space program," he added. "We don't know who Neil Armstrong is yet, who's going to be the one to make this work, but we know we're going to the moon. Everybody engineering things is part of that effort. What Barry has done is more significant than what people imagined. It's close to the Holy Grail when you get it to work in small animals and then you get it to work in large animals. What you have left is to go into humans. It's really got the (gene) delivery field excited because what we all wait on is that affirmation at all levels."

Melanie Fridl Ross | EurekAlert!
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