Cytokine production in motor neurons by poliovirus replicon vector gene delivery

• Published in: Nature biotechnology 2000-09, Vol.18 (9), p.964-969
• Main Authors: Morrow, Casey D, Bledsoe, Andrea W, Jackson, Cheryl A, McPherson, Sylvia
• Format: Article
• Language: English
• Subjects: Agriculture; Animals; Astrocytes - metabolism; Ataxia; Bioinformatics; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Brain Diseases - therapy; CD155 antigen; Central nervous system; Central Nervous System Diseases - therapy; Cytokines; Cytokines - biosynthesis; Cytokines - genetics; Demyelination; Fluorescence; Fundamental and applied biological sciences. Psychology; Gene therapy; Gene transfer; Gene Transfer Techniques; Genetic Therapy - methods; Gliosis; Green fluorescent protein; Green Fluorescent Proteins; Health. Pharmaceutical industry; HeLa Cells; Histology; Humans; Immunohistochemistry; Industrial applications and implications. Economical aspects; Infections; Inoculation; Life Sciences; Luminescent Proteins - genetics; Membrane Proteins; Mice; Mice, Transgenic; Microglia - metabolism; Models, Genetic; Motor neurons; Motor Neurons - metabolism; Myelin; Myelin basic protein; Myelin Basic Protein - metabolism; Myelin Sheath - metabolism; Nervous system; Neurological diseases; Neurons; neurovirology; Oligodendroglia - metabolism; Poliovirus; Poliovirus - genetics; Promoter Regions, Genetic; Proteins; Receptors, Virus - genetics; Signs and symptoms; Spinal cord; Spinal Cord - anatomy & histology; Spinal Cord - metabolism; Time Factors; Transduction, Genetic; Transgenic mice; Trauma; Tumor Necrosis Factor-alpha - genetics; Tumor necrosis factor-TNF; Tumor necrosis factor-α
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/79455

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-α). We detected high-level expression of mTNF-α 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-α 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.