Neuropathy is a common and debilitating complication of diabetes. Several lines of evidence suggest that deficiencies in the tropic factor nerve growth factor (NGF) play a role in the pathogenic sequence leading from insulin deficiency to neuropathy, and studies have shown that treatment with NGF can reverse specific aspects of neuropathy in animal models in the short term. Over the past 5 years, we have made substantial progress in engineering gene transfer vectors from recombinant herpes simplex type 1 (HSV-1), a neurotropic virus which naturally establishes a permanent latent state within neurons. We have also demonstrated that specific viral latency associated promoter sequences (LAP2) are effective in producing prolonged transgene expression from replciation-defective HSV vector genomes persisting in neuron sensory ganglia in a manner similar to latency. This proposal outlines a series of studies in four Specific Aims to test the hypothesis that delivery of NGF by HSV-mediated gene transfer is an effective means of preventing the progression of diabetic neuropathy.
Aim 1 : To establish the parameters of vector-mediated transgene production following both footpad and intestinal inoculation.
Aim 2 : To examine the effect of prior infection with HSV on HSV-mediated transgene production.
Aim 3 : To examine the possibility that HGF expression can be controlled by a drug-inducible transcriptional transactivator produced by the persistent vector in sensory neurons.
Aim 4 : To compare the therapeutic effect of local(intraneuronal) and systemic (following intestinal inoculation) transgene-produced NGF in prevent diabetic neuropathy in STZ diabetic rats using detailed neurophysiologic, morphologic, and behavioral measures of peripheral nerve structure and function. The studies described will provide insight into the mechanism of action of the NGF in the diabetic neuropathy model. Success in achieving these aims could lead directly to the development of a novel therapeutic modality for the treatment and preention of diabetic neuropathy.
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