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 perip heral nerve transition zone and into the spinal cord. This regenerative fai lure leads to a persistent loss of sensory function. To induce axonal growt h across this barrier, we used recombinant adenovirus to express fibroblast growth factor-2 (FGF2), nerve growth factor (NGF), L1 cell adhesion molecu le (L1), or beta -galactosidase (LacZ) within the endogenous glia of the do rsal spinal cord 16 d after injury. Expression of either FGF2 or NGF, but n ot L1 or LacZ, induced robust axonal regeneration into normal as well as ec topic locations within the dorsal spinal cord. This regeneration led to nea r-normal recovery of thermal sensory function. Functional recovery and the majority of regenerating axons within the dorsal horn disappeared with recu tting of the sensory roots. Injections of adenovirus encoding NGF, but not FGF2, also resulted in extensive sprouting of noninjured sensory axons, whi ch we previously demonstrated could cause hyperalgesia and chronic pain. Th us, neurotrophic factor gene therapy administered as late as 16 d after inj ury may serve as a useful treatment to elicit recovery after dorsal root av ulsion; however, the choice of neurotrophin is important to induce selectiv e regeneration of damaged axons.