Peripherally delivered glutamic acid decarboxylase gene therapy for spinal cord injury pain.
Neuropathic pain after spinal cord injury (SCI) represents a difficult problem that is commonly refractory to conventional medical management. To determine if spinal release of gamma-amino butyric acid (GABA) could reduce below-level central neuropathic pain after SCI, we constructed a replication-incompetent herpes simplex virus (HSV)-based vector encoding one isoform of human glutamic acid decarboxylase (GAD67). Dorsal root ganglion (DRG) neurons transduced in vitro or in vivo by subcutaneous inoculation produced GAD and released GABA constitutively. T13 spinal cord hemisection resulted in central neuropathic pain manifested by mechanical allodynia and thermal hyperalgesia. Subcutaneous inoculation of the vector into both feet reduced both manifestations of below-level SCI pain; the vector-mediated effect was partially reversed by intrathecal bicuculline or phaclofen at doses that did not affect thresholds in normal or injured uninoculated animals. Vector-mediated GABA release attenuated the increase in spinal calcitonin gene-related peptide immunoreactivity caused by cord hemisection. These results suggest that HSV-mediated gene transfer to DRG could be used to treat below-level central neuropathic pain after incomplete SCI.
Liu
Jun
J
Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Wolfe
Darren
D
Hao
Shuanglin
S
Huang
Shaohua
S
Glorioso
Joseph C
JC
Mata
Marina
M
Fink
David J
DJ
D000818:Animals; D001418:Baclofen / Q000031:analogs & derivatives* / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000276:immunology; D005727:Ganglia, Spinal / Q000166:cytology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D006930:Hyperalgesia / Q000628:therapy; D007279:Injections, Subcutaneous; D007527:Isoenzymes / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D009474:Neurons / Q000201:enzymology; D010146:Pain / Q000209:etiology; D051381:Rats; D018139:Simplexvirus / Q000235:genetics; D013119:Spinal Cord Injuries / Q000628:therapy*; D014018:Tissue Distribution; D014161:Transduction, Genetic; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D007527:Isoenzymes; C052329:phaclofen; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D001418:Baclofen; D015740:Calcitonin Gene-Related Peptide; D001640:Bicuculline