ADENOVIRUS-MEDIATED TRANSDUCTION WITH HUMAN GLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR GENE PREVENTS METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE-INDUCED DOPAMINE DEPLETION IN STRIATUM OF MOUSE-BRAIN

As a novel trial of neuroprotective therapy of neurodegenerative disea ses, we have constructed a recombinant adenovirus vector (rAdv) bearin g a neurotrophic factor gene to deliver the factor to rescue neurons i n vivo. In the present study, human glial cell line-derived neurotroph ic factor (hGDNF) was chosen to examine the applicability of our strat egy to a mouse model of Parkinson's disease. During the construction o f the rAdv, we found that the strong constitutive hGDNF expression uni t somehow inhibited the appearance of the rAdv. Therefore we adopted a self-contained tetracycline-regulated expression system to acquire an rAdv expressing hGDNF. By analyzing the condition medium of SH-SY5Y c ells infected with our constructed virus vector, we confirmed that bio logically active GDNF was successfully expressed in vitro. For an anim al study, we delivered this virus vector directly to the C57 black mou se brain and then exposed the animal to 1-methyl-4-phenyl-1,2,3,6-tetr ahydropyridine (MPTP) to injure the nigrostriatal dopaminergic neurons . One week after the MPTP exposure, the neuroprotective effect of the virus vector was estimated by measurement of the dopamine content in t he striatum of the mouse brain. The mice that had received our constru cted virus had significantly higher dopamine levels in their striatum, demonstrating that our rAdv expressing hGDNF has therapeutic potentia l to protect the nigrostriatal dopaminergic neurons in vivo. (C) 1997 Academic Press.