title: Enhanced adenoviral gene delivery to motor and dorsal root ganglion neurons following injection into demyelinated peripheral nerves.
abstract: Injection of viral vectors into peripheral nerves may transfer specific genes into their dorsal root ganglion (DRG) neurons and motoneurons. However, myelin sheaths of peripheral axons block the entry of viral particles into nerves. We studied whether mild, transient peripheral nerve demyelination prior to intraneural viral vector injection would enhance gene transfer to target DRG neurons and motoneurons. The right sciatic nerve of C57BL/6 mice was focally demyelinated with 1% lysolecithin, and the left sciatic nerve was similarly injected with saline (control). Five days after demyelination, 0.5 microl of Ad5-GFP was injected into both sciatic nerves at the site of previous injection. The effectiveness of gene transfer was evaluated by counting GFP(+) neurons in the DRGs and ventral horns. After peripheral nerve demyelination, there was a fivefold increase in the number of infected DRG neurons and almost a 15-fold increase in the number of infected motoneurons compared with the control, nondemyelinated side. Focal demyelination reduced the myelin sheath barrier, allowing greater virus-axon contact. Increased CXADR expression on the demyelinated axons facilitated axoplasmic viral entry. No animals sustained any prolonged neurological deficits. Increased gene delivery into DRG neurons and motoneurons may provide effective treatment for amyotrophic lateral sclerosis, pain, and spinal cord injury.
authors.affiliation: Kentucky Spinal Cord Injury Research Center, Louisville, Kentucky, USA.
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yiyan
authors.initials: Y
authors.lastname: Zheng
authors.forename: Yi Ping
authors.initials: YP
authors.lastname: Zhang
authors.forename: Lisa B E
authors.initials: LB
authors.lastname: Shields
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Hu
authors.forename: Panpan
authors.initials: P
authors.lastname: Yu
authors.forename: Darlene A
authors.initials: DA
authors.lastname: Burke
authors.forename: Heming
authors.initials: H
authors.lastname: Wang
authors.forename: Cai
authors.initials: C
authors.lastname: Jun
authors.forename: Jonathan
authors.initials: J
authors.lastname: Byers
authors.forename: Scott R
authors.initials: SR
authors.lastname: Whittemore
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Shields
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000473:pathology*; D004770:Enterovirus; D005260:Female; D005727:Ganglia, Spinal / Q000502:physiology*; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics; D007150:Immunohistochemistry; D008124:Locomotion / Q000502:physiology; D008244:Lysophosphatidylcholines; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000502:physiology*; D009443:Neuritis / Q000139:chemically induced / Q000473:pathology; D009474:Neurons / Q000502:physiology*; D010525:Peripheral Nerves / Q000502:physiology*; D011991:Receptors, Virus / Q000235:genetics; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology; D012677:Sensation / Q000502:physiology
chemical_list: D008244:Lysophosphatidylcholines; D011991:Receptors, Virus; D049452:Green Fluorescent Proteins