Functional regeneration of chronically injured sensory afferents into adult spinal cord after neurotrophin gene therapy.
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 beta-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.
Romero
M I
MI
Department of Physiology, Spinal Cord and Brain Injury Research Center, University of Kentucky, Albert B. Chandler Medical Center, Lexington, Kentucky 40536-0298, USA.
Rangappa
N
N
Garry
M G
MG
Smith
G M
GM
D000256:Adenoviridae / Q000235:genetics; D000344:Afferent Pathways / Q000187:drug effects / Q000503:physiopathology; D000818:Animals; D001369:Axons / Q000187:drug effects; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage* / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D039841:Leukocyte L1 Antigen Complex; D008124:Locomotion / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000235:genetics; D008845:Microinjections; D009409:Nerve Crush; D020932:Nerve Growth Factor / Q000008:administration & dosage* / Q000235:genetics; D019006:Neural Cell Adhesion Molecules / Q000008:administration & dosage / Q000235:genetics; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D012038:Regeneration / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D001616:beta-Galactosidase / Q000008:administration & dosage / Q000235:genetics
D039841:Leukocyte L1 Antigen Complex; D008562:Membrane Glycoproteins; D019006:Neural Cell Adhesion Molecules; D016222:Fibroblast Growth Factor 2; D020932:Nerve Growth Factor; D001616:beta-Galactosidase