With only 1 injection there was a complete reversal of established peripheral neuropathy and restoration of lost nerve endings to their feet. Researchers from the University of Pittsburgh School of Medicine have demonstrated for the first time that gene therapy can reverse diabetic neuropathy. While their studies have so far only involved mice, the results are significant because they provide the earliest evidence that such an approach might some day help people with diabetes, in whom neuropathy is a common complication that causes irreversible nerve damage.
More than two thirds of patients with diabetes develop neuropathy, which generally affects the sensory neurons within the peripheral nervous system and is characterized by such symptoms as numbness, tingling, pins and needles or loss of sensation, most often to the legs and feet. As a result, patients may be unaware of the presence of ulcers or infections or that they’ve experienced injury. No treatments exist that can stop progression of neuropathy, let alone reverse any damage to nerves.
Five weeks after a one-time inoculation, diabetic animals receiving gene therapy had complete reversal of established peripheral neuropathy and restoration of lost nerve endings to their feet, reported James R. Goss, Ph.D., research assistant professor of molecular genetics and biochemistry at the University of Pittsburgh School of Medicine. He and colleagues had previously found the same gene therapy approach could prevent the development of neuropathy in diabetic animals.
While the exact cause of diabetic neuropathy is unknown, there is evidence to suggest it is associated with a deficiency or dysfunction of certain neurotrophic factors, which are proteins essential for the survival and proper function of neurons. Therefore, the Pitt researchers sought to develop a therapy that would shuttle the genes responsible for their production directly into affected neurons. To gain entry into the cells, the team designed vectors of inactivated herpes simplex virus (HSV), which normally infects sensory neurons. The HSV vectors were encoded with genes for one of two neurotrophin factors: nerve growth factor (NFG) and neurotrophin-3 (NT-3).
“Herpes simplex virus appears to be an ideally suited gene therapy vector for diabetic neuropathy, in part because very little of the virus is needed to get inside the cell. But in addition, an important advantage with this approach is that we can deliver the gene directly and solely to affected neurons, without bombarding the entire the nervous system,” explained Dr. Goss.
In their study, the researchers induced diabetes in mice, which resulted in the development of peripheral neuropathy within six weeks. Once neuropathy was established, they treated two groups with gene therapy — one received the vector encoded for NGF and a second group received the vector encoded with NT-3. To compare outcomes, another group of diabetic animals was treated with the HSV vector encoded for a gene with no therapeutic value, and a fourth group received no treatment. Five weeks after inoculation, the neuropathy was reevaluated using measurements of heat sensitivity and the ability of nerves in the feet to conduct electrical impulses. In diabetic animals treated with either the NGF or NT-3 vectors, signs of neuropathy had disappeared, whereas in the untreated diabetic animals and the diabetic animals treated with the “empty” vector, neuropathy was still present.
Results of another Pitt study from the same group, found that genes introduced by HSV vectors were still expressed six months after single inoculation and could still protect against the development of neuropathy. That study looked at gene expression for NT-3 and two other neurotrophic factors.
Their research was supported by the National Institutes of Health, the Veterans Affairs Administration and the Juvenile Diabetes Research Foundation International. presented today at the 34th Annual Meeting of the Society for Neuroscience, being held Oct. 23 – 27 in San Diego.
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