We have developed recombinant, replication-incompetent, genomic herpes simplex virus (HSV)-based vectors for gene transfer to the nervous system. In the previous period of funding we have demonstrated that HSV- mediated expression of neurotrophin-3 (NT-3), vascular endothelial growth factor (VEGF), or erythropoietin (EPO) in dorsal root ganglion (DRG) in vivo prevents the progression of neuropathy in mice with streptozotocin (STZ)-induced diabetes. In this competing renewal, we will continue to exploit the natural tropism of HSV vectors for peripheral sensory neurons of the (DRG) to further test the hypothesis that gene transfer of neuroprotective factors to the DRG by means of an HSV-based vector can be used to prevent the progression of diabetic neuropathy, with the ultimate aim of developing a therapy that will be effective for the treatment of human neuropathy.
Four specific aims are described. (1) to determine whether HSV-mediated neuroprotective factor expression prevents the loss of DRG neurons in the streptozocin model of type 1 diabetes;(2) to examine the effect of HSV-mediated delivery of neuroprotective factors in the treatment of diabetic neuropathy in the db/db mouse model of type 2 diabetes;(3) to construct a vector with a regulatable switch to control transgene expression safely;and, (4) to test the effect of intermittent regulated protective factor expression on the progression of diabetic neuropathy in the STZ-diabetic and db/db mouse. Project Narrative Relevance to Public Health: Neuropathy is an important and often disabling complication of both type 1 and type 2 diabetes mellitus, and there are no currently available treatments that are effective in preventing the progression of the complication. These studies are designed to develop novel agents that could be used to treat the disease effectively.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038850-12
Application #
8258766
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Gwinn, Katrina
Project Start
1999-07-23
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
12
Fiscal Year
2012
Total Cost
$325,850
Indirect Cost
$111,475
Name
University of Michigan Ann Arbor
Department
Neurology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Ortmann, Kathryn L Maier; Chattopadhyay, Munmun (2014) Decrease in neuroimmune activation by HSV-mediated gene transfer of TNF? soluble receptor alleviates pain in rats with diabetic neuropathy. Brain Behav Immun 41:144-51
Wu, Zetang; Wang, Shiyong; Gruber, Sandy et al. (2013) Full-length membrane-bound tumor necrosis factor-* acts through tumor necrosis factor receptor 2 to modify phenotype of sensory neurons. Pain 154:1778-82
Simonato, Michele; Bennett, Jean; Boulis, Nicholas M et al. (2013) Progress in gene therapy for neurological disorders. Nat Rev Neurol 9:277-91
Murthy, Rachana; Kim, Jeeyong; Sun, Xiankui et al. (2013) Post-transcriptional regulation of GABAB receptor and GIRK1 channels by Nogo receptor 1. Mol Brain 6:30
Sun, J; Liu, S; Mata, M et al. (2012) Transgene-mediated expression of tumor necrosis factor soluble receptor attenuates morphine tolerance in rats. Gene Ther 19:101-8
Chattopadhyay, Munmun; Zhou, Zhigang; Hao, Shuanglin et al. (2012) Reduction of voltage gated sodium channel protein in DRG by vector mediated miRNA reduces pain in rats with painful diabetic neuropathy. Mol Pain 8:17
Fink, David J; Wechuck, James; Mata, Marina et al. (2011) Gene therapy for pain: results of a phase I clinical trial. Ann Neurol 70:207-12
Zhou, Zhigang; Kim, Jeeyong; Insolera, Ryan et al. (2011) Rho GTPase regulation of ýý-synuclein and VMAT2: implications for pathogenesis of Parkinson's disease. Mol Cell Neurosci 48:29-37
Wu, Zetang; Mata, Marina; Fink, David J (2011) Prevention of diabetic neuropathy by regulatable expression of HSV-mediated erythropoietin. Mol Ther 19:310-7
Zheng, Wenwen; Ouyang, Handong; Zheng, Xuexing et al. (2011) Glial TNFýý in the spinal cord regulates neuropathic pain induced by HIV gp120 application in rats. Mol Pain 7:40

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