Response of aged parkinsonian monkeys to in vivo gene transfer of GDNF.
This study assessed the potential for functional and anatomical recovery of the diseased aged primate nigrostriatal system, in response to trophic factor gene transfer. Aged rhesus monkeys received a single intracarotid infusion of MPTP, followed one week later by MRI-guided stereotaxic intrastriatal and intranigral injections of lentiviral vectors encoding for glial derived neurotrophic factor (lenti-GDNF) or beta-galactosidase (lenti-LacZ). Functional analysis revealed that the lenti-GDNF, but not lenti-LacZ treated monkeys displayed behavioral improvements that were associated with increased fluorodopa uptake in the striatum ipsilateral to lenti-GDNF treatment. GDNF ELISA of striatal brain samples confirmed increased GDNF expression in lenti-GDNF treated aged animals that correlated with functional improvements and preserved nigrostriatal dopaminergic markers. Our results indicate that the aged primate brain challenged by MPTP administration has the potential to respond to trophic factor delivery and that the degree of neuroprotection depends on GDNF levels.
Emborg
M E
ME
Preclinical Parkinson's Research Program, Wisconsin National Primate Research Center, University of Wisconsin - Madison, 1223 Capitol Court, Madison, WI 53715, USA. emborg@primate.wisc.edu
Moirano
J
J
Raschke
J
J
Bondarenko
V
V
Zufferey
R
R
Peng
S
S
Ebert
A D
AD
Joers
V
V
Roitberg
B
B
Holden
J E
JE
Koprich
J
J
Lipton
J
J
Kordower
J H
JH
Aebischer
P
P
D000367:Age Factors; D000375:Aging / Q000235:genetics; D000818:Animals; D003342:Corpus Striatum / Q000737:chemistry / Q000378:metabolism; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000627:therapeutic use; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics*; D016086:Lentivirus / Q000235:genetics; D008253:Macaca mulatta; D008297:Male; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000503:physiopathology / Q000517:prevention & control; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D020127:Recovery of Function / Q000187:drug effects / Q000235:genetics
D051100:Glial Cell Line-Derived Neurotrophic Factor