HSV-mediated gene transfer of vascular endothelial growth factor to dorsal root ganglia prevents diabetic neuropathy

Chattopadhyay, Munmun; Krisky, David; Wolfe, Darren; Jc, Glorioso; Mata, Marina; Dj, Fink

doi:10.1038/sj.gt.3302533

Cited by 73 publications

(59 citation statements)

References 52 publications

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“…Maximal expression of VEGF was observed in the epidermis consistent with previous studies (22), particularly by keratinocytes (23,24). Although these results do not directly imply cause and effect, they do provide the first clinical data in support of a link demonstrated in experimental diabetic neuropathy (3,4). Tissue hypoxia has been proposed to upregulate HIF-1␣ expression (25), which is considered to be the main stimulator of VEGF-A synthesis.…”

Section: Dermal Microvessel Density and Vasodilator Responsessupporting

confidence: 78%

“…These data demand further quantitative studies assessing VEGF protein and/or mRNA levels to establish a more direct causal link between VEGF and diabetic neuropathy to provide a basis for the beneficial effects reported to date (3)(4)(5)30).…”

Section: Dermal Microvessel Density and Vasodilator Responsesmentioning

confidence: 99%

“…Vascular endothelial growth factor (VEGF) has been shown to have neurotrophic properties (2). Recently herpes simplex virus vector-mediated VEGF prevented a reduction in sensory nerve amplitude and loss of intraepidermal nerve fibers (IENFs) (3). Intramuscular administration of an engineered zinc finger transcription factor, which activates transcription of all major VEGF-A isoforms, improved sensory and motor nerve conduction velocities (4) and yielded a positive indication in a phase 1 clinical trial (5) for establishing a larger phase 2 trial with additional end points including IENF assessment.…”

mentioning

confidence: 99%

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Reduced Vascular Endothelial Growth Factor Expression and Intra-Epidermal Nerve Fiber Loss in Human Diabetic Neuropathy

Quattrini

Jeziorska²,

Boulton³

et al. 2008

Diabetes Care

108

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OBJECTIVE -To assess the relevance of vascular endothelial growth factor (VEGF) in the maintenance of peripheral nerve integrity in diabetic neuropathy we have assessed the expression of VEGF and intra-epidermal nerve fiber density (IENFD) in skin biopsy samples from diabetic patients.RESEARCH DESIGN AND METHODS -Fifty-three diabetic patients and 12 nondiabetic control subjects underwent neurological evaluation, electrophysiology, quantitative sensory, and autonomic function testing. Dermal blood flow responses were evaluated with laser Doppler flowmetry. Skin biopsies were performed on the dorsum of the foot, and IENFD was quantified and compared with the expression of vascular endothelial growth factor A (VEGF-A), its receptor vascular endothelial growth factor receptor 2 (VEGFR-2), hypoxia-inducible factor 1␣ (HIF-1␣), and microvessel density.RESULTS -IENFD decreased progressively with increasing severity of diabetic neuropathy (P Ͻ 0.001). The dermal blood flow response to acetylcholine was reduced in diabetic patients with mild and moderate neuropathy (P Ͻ 0.01), and the intensity of staining for epidermal VEGF-A was significantly reduced in diabetic patients compared with control subjects (P Ͻ 0.01). Epidermal HIF-1␣ and VEGFR-2 expression did not differ between groups.CONCLUSIONS -Progressive endothelial dysfunction, a reduction in VEGF expression, and loss of intra-epidermal nerve fibers occurs in the foot skin of diabetic patients with increasing neuropathic severity.

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Section: Dermal Microvessel Density and Vasodilator Responsessupporting

confidence: 78%

Section: Dermal Microvessel Density and Vasodilator Responsesmentioning

confidence: 99%

mentioning

confidence: 99%

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Reduced Vascular Endothelial Growth Factor Expression and Intra-Epidermal Nerve Fiber Loss in Human Diabetic Neuropathy

Quattrini

Jeziorska²,

Boulton³

et al. 2008

Diabetes Care

108

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“…The use of the herpes simplex virus vector-mediated gene transfer of the vascular endothelial growth factor in a mouse model of diabetic neuropathy provided promising results on the prevention of neuronal dysfunctions (93).…”

Section: Secondary Interventionsmentioning

confidence: 99%

New insights in diabetic autonomic neuropathy in children and adolescents

Verrotti

Loiacono

Mohn

et al. 2009

European Journal of Endocrinology

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Diabetic autonomic neuropathy (DAN) represents a major complication of diabetes mellitus but there is considerable uncertainty about its incidence, prevalence, pathogenesis, diagnosis, and prognosis. There are conflicting opinions about the pathogenesis of DAN: the 'classical hypothesis' has been supplemented by some new insights. Clinical symptoms of autonomic neuropathy do not generally occur until long after the onset of diabetes. DAN seems to be detectable even in asymptomatic children and adolescents with diabetes and is associated with the most serious consequences, such as cardiovascular dysfunction. Because of its association with a variety of adverse outcomes, including cardiovascular deaths, cardiovascular autonomic neuropathy is the most clinically important and well-studied form of DAN. No form of therapy in DAN has been identified that provides unequivocal, safe, and effective stabilization or reversal of the condition, just a near normal control of blood glucose in the early years after the onset of diabetes that may delay the development of clinically significant nerve impairment. This article reviews recent developments in knowledge of epidemiology, pathogenesis, clinical symptoms, diagnosis, and therapy of DAN.

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“…In a mouse model of streptozotocin (STZ)-induced type 1 diabetes, we demonstrated that s.c. inoculation of HSV-based vectors expressing NGF [21] or VEGF [22] 2 weeks after inoculation of STZ can prevent development of neuropathy measured 6 weeks later. These proof-of-principle studies confirm the effectiveness of this mode of HSV-mediated gene transfer, but the time course in those studies was short.…”

mentioning

confidence: 99%

Prolonged preservation of nerve function in diabetic neuropathy in mice by herpes simplex virus-mediated gene transfer

Chattopadhyay¹,

Mata²,

Goss³

et al. 2007

Diabetologia

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Aims/hypothesis The aim of this study was to determine whether prolonged expression of neurotrophin-3 (NT-3) in mice, achieved by herpes simplex virus (HSV)-mediated gene transfer with gene expression under the control of an HSV latency promoter, can provide protection against the progression of diabetic neuropathy over a 6 month period. Materials and methods Mice with diabetes induced by streptozotocin were inoculated s.c. into both hind feet with a non-replicating HSV vector containing the coding sequence for NT-3 under the control of the HSV latencyassociated promoter 2 (LAP2) elements or with a control vector. Nerve function was evaluated by electrophysiological and behavioural measures over the course of 6 months after the onset of diabetes. Results Animals inoculated with the NT-3-expressing vector, but not animals inoculated with control vector, showed preservation of sensory and motor nerve amplitude and conduction velocity measured electrophysiologically, small fibre sensory function assessed by withdrawal from heat, autonomic function measured by pilocarpine-induced sweating, skin innervation assessed by protein gene product 9.5 staining of axons, and density of calcitonin gene-related peptide terminals in the spinal cord measured by immunohistochemistry 5.5 months after vector inoculation. Conclusions/interpretation These results indicate that the continuous production of NT-3 by LAP2-driven expression of the transgene from an HSV vector over a 6 month period protects against progression of diabetic neuropathy in mice, and provide a proof-of-principle demonstration for the development of a novel therapy for preventing the progression of diabetic neuropathy.

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HSV-mediated gene transfer of vascular endothelial growth factor to dorsal root ganglia prevents diabetic neuropathy

Cited by 73 publications

References 52 publications

Reduced Vascular Endothelial Growth Factor Expression and Intra-Epidermal Nerve Fiber Loss in Human Diabetic Neuropathy

Reduced Vascular Endothelial Growth Factor Expression and Intra-Epidermal Nerve Fiber Loss in Human Diabetic Neuropathy

New insights in diabetic autonomic neuropathy in children and adolescents

Prolonged preservation of nerve function in diabetic neuropathy in mice by herpes simplex virus-mediated gene transfer

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