Safety evaluation of AAV2-GDNF gene transfer into the dopaminergic nigrostriatal pathway in aged and parkinsonian rhesus monkeys.
We evaluated neuropathological findings in two studies of AAV2-GDNF efficacy and safety in naive aged (>20 years) or MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned rhesus macaques. In the first study, a total of 17 animals received one of two doses of AAV2-GDNF into either putamen or substantia nigra (SN). To control for surgical variables, all animals received identical putaminal and nigral infusions in which phosphate-buffered saline was substituted for vector as appropriate. All 17 aged monkeys were studied for 6 months before necropsy. In a separate study, 11 MPTP-lesioned rhesus macaques with extensive lesions in the right SN and mild lesions in the left SN received bilateral infusions of AAV2-GDNF (9.9 x 10(11) vector genomes) or PBS into the putamen and were then studied for up to 14 months. In the current analysis, we addressed safety issues regarding AAV2-GDNF administration. An extensive series of assessments of in-life behavioral and clinical parameters was conducted. No overt histopathology or immune responses were detected in any experimental monkey. However, the delivery of AAV2-GDNF to the SN of aged monkeys caused a marked and significant loss of body weight (-19.4%). No weight loss was observed in the MPTP-lesioned monkeys despite bilateral axonal transport of glial cell line-derived neurotrophic factor (GDNF) to the SN from the putamen. These findings indicate that putaminal administration of AAV2-GDNF by convection-enhanced delivery shows therapeutic promise without any apparent side effects. Importantly, nigral administration of AAV2-GDNF caused significant weight loss that raises substantial concern for clinical application of this approach.
Su
Xiaomin
X
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94103, USA.
Kells
Adrian P
AP
Huang
Eric J
EJ
Lee
Han S
HS
Hadaczek
Piotr
P
Beyer
Janine
J
Bringas
John
J
Pivirotto
Philip
P
Penticuff
Janine
J
Eberling
Jamie
J
Federoff
Howard J
HJ
Forsayeth
John
J
Bankiewicz
Krystof S
KS
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000367:Age Factors; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D018014:Gene Transfer Techniques / Q000009:adverse effects*; D015316:Genetic Therapy; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008253:Macaca mulatta; D010300:Parkinson Disease / Q000473:pathology / Q000628:therapy*; D010302:Parkinson Disease, Secondary / Q000473:pathology / Q000628:therapy*; D013378:Substantia Nigra / Q000378:metabolism*
D015259:Dopamine Agents; D051100:Glial Cell Line-Derived Neurotrophic Factor; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine