NEUROPROTECTION OF SPINAL MOTONEURONS FOLLOWING TARGETED TRANSDUCTIONWITH AN ADENOVIRAL VECTOR CARRYING THE GENE FOR GLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR

Application of neurotrophic factors (NFs) to the cut stump of peripher al nerves confers transient (1- to a-week) neuroprotection of motoneur ons from axotomy-induced death in neonates. We tested whether lumbar s pinal motoneurons would be protected from axotomy-induced death when t hey were genetically modified to produce NFs in situ. Adenoviral (Adv) vectors carrying neurotrophic factor genes under control of the Rous sarcoma virus long terminal repeat promoter (Adv.RSV-nf) or a control vector containing the beta-galactosidase (beta-gal) gene (Adv.RSV-beta gal) was injected into the hindlimb muscles of neonatal rats. The Adv were taken up by peripheral nerves and transported to lumbar spinal c ord motoneurons where the transgenes were expressed. A fraction (18%) of the motoneurons that projected through the sciatic nerve were trans duced with Adv.RSV-beta gal. Expression of Adv.RSV-beta gal was detect ed in motoneurons after 7 days and 3 weeks, with no evidence of vector - or beta-gal-induced toxicity or inflammation. PCR, immunocytochemist ry, and RT-PCR demonstrated transport of the Adv.RSV-nf vectors to mot oneurons and their expression. After retrograde transport of an Adv.RS V-nf vector carrying the gene for glial cell line-derived neurotrophic factor, a substantial proportion of the sciatic nerve motoneurons wer e resistant to axotomy-induced death 7 days and 3 weeks after sciatic nerve transection (56 and 44%, respectively), compared to Adv.RSV-beta gal controls (2.5 and 0%, respectively). (C) 1998 Academic Press.