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The Journal of Neuroscience, November 1, 2001, 21(21):8408-8416

Functional Regeneration of Chronically Injured Sensory Afferents into Adult Spinal Cord after Neurotrophin Gene Therapy

Mario I. Romero², Nagarathnamma Rangappa¹, Mary G. Garry², and George M. Smith¹

¹ Department of Physiology, Spinal Cord and Brain Injury Research Center, University of Kentucky, Albert B. Chandler Medical Center, Lexington, Kentucky 40536-0298, and ² Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9068

Lesioned axons within the dorsal roots fail to regenerate through the peripheral nerve transition zone and into the spinal cord. This regenerative failure leads to a persistent loss of sensory function. To induce axonal growth across this barrier, we used recombinant adenovirus to express fibroblast growth factor-2 (FGF2), nerve growth factor (NGF), L1 cell adhesion molecule (L1), or -galactosidase (LacZ) within the endogenous glia of the dorsal spinal cord 16 d after injury. Expression of either FGF2 or NGF, but not L1 or LacZ, induced robust axonal regeneration into normal as well as ectopic locations within the dorsal spinal cord. This regeneration led to near-normal recovery of thermal sensory function. Functional recovery and the majority of regenerating axons within the dorsal horn disappeared with recutting of the sensory roots. Injections of adenovirus encoding NGF, but not FGF2, also resulted in extensive sprouting of noninjured sensory axons, which we previously demonstrated could cause hyperalgesia and chronic pain. Thus, neurotrophic factor gene therapy administered as late as 16 d after injury may serve as a useful treatment to elicit recovery after dorsal root avulsion; however, the choice of neurotrophin is important to induce selective regeneration of damaged axons.

Key words: gene therapy; regeneration; neurotrophins; functional recovery; spinal cord; adenovirus

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21218408-09$05.00/0

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