ITTSBURGH, Oct. 28 -- The successful clinical delivery of a therapeutic gene for peripheral neuropathy could treat this form of nerve damage experienced by millions of individuals as a result of disease or drug exposure. In new studies of two different animal models, University of Pittsburgh investigators for the first time have shown that a modified herpes virus shuttles a therapeutic gene not only to neurons that it typically enters, but also to non-neuronal cells and in turn provides an important long-term source of protein called nerve growth factor (NGF). Furthermore, they found that the newly manufactured NGF enters the bloodstream, where it can travel to and potentially repair nerve-damaged sites throughout the body. These results are being presented, Thursday, Oct. 28, by research associate Darren Wolfe, Ph.D., and the Pittsburgh team at the annual meeting of the Society for Neuroscience in Miami.
The Pittsburgh investigators most recently showed that the modified herpes virus enters bladder nerve cells and reverses incontinence in rats due to nerve damage.
"These new findings are important for us to understand how this gene therapy may work in a clinical setting," remarked William Goins, Ph.D., assistant professor of molecular genetics and biochemistry at the University of Pittsburgh School of Medicine. "Our results show that we could provide low-level, continuous production of nerve growth factor that could circulate throughout the body and potentially repair nerves at sites far from where the gene is initially delivered. This therapeutic strategy could be extremely useful in the clinic."
Previous patient studies in which nerve-growth factor was injected intravenously have failed because the body rapidly breaks down this protein, and the large doses of this agent needed to circumvent this problem result in unwanted side effects. Long-term, low-level production of freely circulating nerve growth factor may be the solution for patients with peripheral neuropathy in arms and legs resulting from diabetes or exposure to chemotherapy, for instance.
Peripheral neuropathy is a broad term describing damage to nerves that are important in relaying sensory signals from body parts like the skin, muscles and internal organs to the central nervous system. As a result, parts of the body may function inappropriately or not at all. Diseases such as diabetes or rheumatoid arthritis can cause peripheral neuropathy, as can infections, lead poisoning or exposure to other drugs.
In their studies, Dr. Wolfe and the Pittsburgh team used a herpes virus incapable of replicating itself to deliver the gene for NGF to knee joints of rabbits and non-human primates. The researchers used two types of herpes virus, one engineered with a genetic component, or promoter, that turns on the NGF gene in neurons and one engineered with another promoter that turns on the NGF gene in cells other than neurons. Surprisingly, they found that both promoters were active, suggesting that the NGF protein was manufactured in non-neuronal cells. In fact, they found that cells of ligaments and tendons within the joints, as well as neuronal cells, made NGF.
Currently, the Pittsburgh investigators are studying the use of a herpes virus to deliver the NGF gene to animals with drug-induced or naturally occurring peripheral neuropathies where systemic delivery of the NGF protein could preserve the function of neurons.