Towards a neuroprotective gene therapy for Parkinson's disease: use of adenovirus, AAV and lentivirus vectors for gene transfer of GDNF to the nigrostriatal system in the rat Parkinson model

During the last few years. recombinant viral vectors derived from adenoviru s (Ad), adeno-associated virus (AAV) or lentivirus (LV) have been developed into highly effective vehicles for gene transfer to the adult central nerv ous system. In recent experiments, in the rat model of Parkinson's disease, all three vector systems have been shown to be effective for long-term del ivery of glial cell line-derived neurotrophic factor (GDNF) at biologically relevant levels in the nigrostriatal system. Injection of the GDNF encodin g vectors into either striatum or substantia nigra thus makes it possible t o obtain a regionally restricted over-expression of GDNF within the nigrost riatal system that is sufficient to block the toxin-induced degeneration of the nigral dopamine neurons. Injection of GDNF vectors in the striatum, in particular, is effective not only in rescuing the cell bodies in the subst antia nigra, but also in preserving the nigrostriatal projection and a func tional striatal dopamine innervation in the rat Parkinson model. Long-term experiments using AAV-GDNF and LV-GDNF vectors show. moreover, that sustain ed GDNF delivery over 3-6 months can promote regeneration and significant f unctional recovery in both 6-OHDA-lesioned rats and MPTP-lesioned monkeys. The impressive efficacy of the novel AAV and LV vectors in rodent and prima te Parkinson models suggests that the time may now be ripe to explore these vector systems as tools for neuroprotective treatments in patients with Pa rkinson's disease. (C) 2000 Elsevier Science B.V. All rights reserved.