HSV-1-mediated NGF delivery delays nociceptive deficits in a genetic model of diabetic neuropathy

• Published in: Experimental neurology Vol. 198; no. 1; pp. 260 - 270
• Main Authors: Walwyn, W.M., Matsuka, Y., Arai, D., Bloom, D.C., Lam, H., Tran, C., Spigelman, I., Maidment, N.T.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.03.2006; Elsevier
• Subjects: Action Potentials - physiology; Age Factors; Animals; Associated diseases and complications; Behavior, Animal; Biological and medical sciences; Blotting, Northern - methods; Cell Count - methods; Cranial nerves. Spinal roots. Peripheral nerves. Autonomic nervous system. Gustation. Olfaction; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - genetics; Diabetic Nephropathies - therapy; Diabetic neuropathy; Disease Models, Animal; Dose-Response Relationship, Radiation; Electric Stimulation - methods; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Ganglia, Spinal - physiopathology; Genetic Therapy; Genetic Vectors - physiology; Herpes Simplex Virus-1; Immunohistochemistry - methods; Lepr db/db mice; Male; Medical sciences; Mice; Mice, Inbred C57BL; Nerve Fibers - physiology; Nerve Fibers - radiation effects; Nerve growth factor; Nerve Growth Factors - physiology; Nervous system (semeiology, syndromes); Neurology; Nociception; Pain Measurement - methods; Reaction Time; Receptor, Nerve Growth Factor - metabolism; Reverse Transcriptase Polymerase Chain Reaction - methods; RNA, Messenger - metabolism; Simplexvirus - physiology; Substance P - metabolism; Nociception; Herpes Simplex Virus-1; Diabetic neuropathy; Nerve growth factor; Lepr db/db mice; Endocrinopathy; Phase III trial; Neurotrophin; Animal model; Peripheral nerve; Spinal cord; Alphaherpesvirinae; Central nervous system; Neuropathy; Hypoalgesia; Neuropeptide; Human herpesvirus 1; Subcutaneous administration; Herpesvirus hominis; Vector; Nervous system diseases; Substance P; Herpesviridae; Diabetes mellitus; Rodentia; Longevity; Virus; Vertebrata; Mammalia; Treatment; Mouse; Dysfunction; Animal; Spinal ganglion; Gene therapy; Tachykinin
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2005.12.006

A previous phase III clinical trial failed to show significant therapeutic benefit of repeated subcutaneous nerve growth factor (NGF) administration in the treatment of diabetic neuropathy. Animal studies have since shown that site-specific viral-mediated expression of NGF in the lumbar dorsal root ganglia prevents peripheral nerve dysfunction associated with chemically induced neuropathy. Using a Herpes simplex virus expression vector, we have investigated the effect of localized NGF expression in a genetic mouse model of progressive diabetic neuropathy, the +/+ Leprdb mouse. We found that site-specific delivery of NGF initially delayed the appearance of hypoalgesia, assessed by the Hargreaves test, by 1 month and effectively attenuated this deficit for 2 months over the approximately 10 months normal life-span of these animals. Once the disease progressed into its more severe stages, NGF, although still capable of altering the electrophysiological profile of the sensory A- and C-fibers and influencing the expression of p75 and substance P in the dorsal root ganglia, could no longer maintain normal nociception. These data suggest that maximal therapeutic benefit in future NGF-based gene therapy trials will be gained from early applications of such viral-mediated neurotrophin delivery.