Long-term neuroprotection achieved with latency-associated promoter-driven herpes simplex virus gene transfer to the peripheral nervous system.
We examined the ability of the herpes simplex virus (HSV) latency-associated promoter (LAP2) to drive biologically relevant prolonged transgene expression in the peripheral nervous system. Rat dorsal root ganglia were transduced in vivo by subcutaneous inoculation of replication-incompetent HSV-based vectors containing nerve growth factor (NGF) or neurotrophin-3 (NT-3) under the control of LAP2 (vectors SLN and QLNT3, respectively) and vector SHN expressing NGF under the control of the human cytomegalovirus immediate early promoter. Twenty-four weeks later a pure sensory neuropathy was induced by overdose of pyridoxine (PDX), and the animals were assessed 6 months after inoculation. Inoculation of SLN, but not SHN, attenuated the nerve damage caused by PDX and protected foot sensory amplitude, H-wave amplitude, and behavioral measures of proprioceptive function. QLNT3 was more effective than SLN in preserving the largest myelinated fibers from degeneration. These results indicate that expression of NGF or NT-3 driven by LAP2 is sufficient to prevent the development of neuropathy 6 months after vector inoculation in rats.
Chattopadhyay
Munmun
M
Department of Neurology, University of Michigan Health System and Neurology Service, VA Ann Arbor Healthcare System, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0316, USA.
Wolfe
Darren
D
Mata
Marina
M
Huang
Shaohua
S
Glorioso
Joseph C
JC
Fink
David J
DJ
D000818:Animals; D004594:Electrophysiology; D015967:Gene Expression Regulation, Viral; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D018696:Neuroprotective Agents; D020933:Neurotrophin 3 / Q000502:physiology*; D010523:Peripheral Nervous System Diseases / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000502:physiology; D018139:Simplexvirus / Q000235:genetics*; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism
C477254:LAT protein, Human herpesvirus 2; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D020933:Neurotrophin 3; D014764:Viral Proteins