Cytokine production in motor neurons by poliovirus replicon vector gene delivery.
Poliovirus replicon vectors transiently express foreign proteins selectively in motor neurons of the anterior horn of the spinal cord. Here we intraspinally inoculated mice transgenic for the poliovirus receptor (PVR) with replicons encoding murine tumor necrosis factor alpha (mTNF-alpha). We detected high-level expression of mTNF-alpha in the spinal cords of these animals at 8-12 h post inoculation; this returned to background by 72 h. The mice exhibited ataxia and tail atony, whereas animals given a replicon encoding green fluorescent protein (GFP) exhibited no neurological symptoms. Histology of spinal cords from mice given the replicon encoding mTNF-alpha revealed neuronal chromatolysis, reactive astrogliosis, decreased expression of myelin basic protein, and demyelination. These animals recovered with only slight residual damage. This study shows that replicon vectors have potential for targeted delivery of therapeutic proteins to the central nervous system and provide a new approach for treatment of spinal cord trauma and neurological disease.
Bledsoe
A W
AW
Department of Microbiology, University of Alabama at Birmingham, 35294, USA.
Jackson
C A
CA
McPherson
S
S
Morrow
C D
CD
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001927:Brain Diseases / Q000628:therapy*; D002493:Central Nervous System Diseases / Q000628:therapy*; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D008164:Luminescent Proteins / Q000235:genetics; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D008957:Models, Genetic; D009046:Motor Neurons / Q000378:metabolism*; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D017955:Poliovirus / Q000235:genetics; D011401:Promoter Regions, Genetic; D011991:Receptors, Virus / Q000235:genetics; D013116:Spinal Cord / Q000033:anatomy & histology / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D016207:Cytokines; D008164:Luminescent Proteins; D008565:Membrane Proteins; D004676:Myelin Basic Protein; D011991:Receptors, Virus; D014409:Tumor Necrosis Factor-alpha; C066100:poliovirus receptor; D049452:Green Fluorescent Proteins