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!
Staphylococcus aureus: A new mechanism involved in virulence and antibiotic resistance
23.03.2018 | Institut Pasteur
Scientists develop tiny tooth-mounted sensors that can track what you eat
22.03.2018 | Tufts University
Satellites in near-Earth orbit are at risk due to the steady increase in space debris. But their mission in the areas of telecommunications, navigation or weather forecasts is essential for society. Fraunhofer FHR therefore develops radar-based systems which allow the detection, tracking and cataloging of even the smallest particles of debris. Satellite operators who have access to our data are in a better position to plan evasive maneuvers and prevent destructive collisions. From April, 25-29 2018, Fraunhofer FHR and its partners will exhibit the complementary radar systems TIRA and GESTRA as well as the latest radar techniques for space observation across three stands at the ILA Berlin.
The "traffic situation" in space is very tense: the Earth is currently being orbited not only by countless satellites but also by a large volume of space...
An international team of researchers has discovered a new anti-cancer protein. The protein, called LHPP, prevents the uncontrolled proliferation of cancer cells in the liver. The researchers led by Prof. Michael N. Hall from the Biozentrum, University of Basel, report in “Nature” that LHPP can also serve as a biomarker for the diagnosis and prognosis of liver cancer.
The incidence of liver cancer, also known as hepatocellular carcinoma, is steadily increasing. In the last twenty years, the number of cases has almost doubled...
In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.
Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...
Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.
They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...
A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...
23.03.2018 | Event News
19.03.2018 | Event News
16.03.2018 | Event News
23.03.2018 | Materials Sciences
23.03.2018 | Agricultural and Forestry Science
23.03.2018 | Physics and Astronomy