Clinically relevant effects of convection-enhanced delivery of AAV2-GDNF on the dopaminergic nigrostriatal pathway in aged rhesus monkeys.
Growth factor therapy for Parkinson's disease offers the prospect of restoration of dopaminergic innervation and/or prevention of neurodegeneration. Safety and efficacy of an adeno-associated virus (AAV2) encoding human glial cell-derived neurotrophic factor (GDNF) was investigated in aged nonhuman primates. Positron emission tomography with 6-[(18)F]-fluoro-l-m-tyrosine (FMT-PET) in putamen was assessed 3 months before and after AAV2 infusion. In the right putamen, monkeys received either phosphate-buffered saline or low-dose (LD) or high-dose (HD) AAV2-GDNF. Monkeys that had received putaminal phosphate-buffered saline (PBS) infusions additionally received either PBS or HD AAV2-GDNF in the right substantia nigra (SN). The convection-enhanced delivery method used for infusion of AAV2-GDNF vector resulted in robust volume of GDNF distribution within the putamen. AAV2-GDNF increased FMT-PET uptake in the ipsilateral putamen as well as enhancing locomotor activity. Within the putamen and caudate, the HD gene transfer mediated intense GDNF fiber and extracellular immunoreactivity (IR). Retrograde and anterograde transport of GDNF to other brain regions was observed. AAV2-GDNF did not significantly affect dopamine in the ipsilateral putamen or caudate, but increased dopamine turnover in HD groups. HD putamen treatment increased the density of dopaminergic terminals in these regions. HD treatments, irrespective of the site of infusion, increased the number of nonpigmented TH-IR neurons in the SN. AAV2-GDNF gene transfer does not appear to elicit adverse effects, delivers therapeutic levels of GDNF within target brain areas, and enhances utilization of striatal dopamine and dopaminergic nigrostriatal innervation.
Johnston
Louisa C
LC
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94103, USA.
Eberling
Jamie
J
Pivirotto
Philip
P
Hadaczek
Piotr
P
Federoff
Howard J
HJ
Forsayeth
John
J
Bankiewicz
Krystof S
KS
D000367:Age Factors; D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D018014:Gene Transfer Techniques / Q000009:adverse effects; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics*; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000628:therapy*; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D051100:Glial Cell Line-Derived Neurotrophic Factor; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine