Differential transduction following basal ganglia administration of distinct pseudotyped AAV capsid serotypes in nonhuman primates.
We examined the transduction efficiency of different adeno-associated virus (AAV) capsid serotypes encoding for green fluorescent protein (GFP) flanked by AAV2 inverted terminal repeats in the nonhuman primate basal ganglia as a prelude to translational studies, as well as clinical trials in patients with Parkinson's disease (PD). Six intact young adult cynomolgus monkeys received a single 10 microl injection of AAV2/1-GFP, AAV2/5-GFP, or AAV2/8-GFP pseudotyped vectors into the caudate nucleus and putamen bilaterally in a pattern that resulted in each capsid serotype being injected into at least four striatal sites. GFP immunohistochemistry revealed excellent transduction rates for each AAV pseudotype. Stereological estimates of GFP+ cells within the striatum revealed that AAV2/5-GFP transduces significantly higher number of cells than AAV2/8-GFP (P < 0.05) and there was no significant difference between AAV2/5-GFP and AAV2/1-GFP (P = 0.348). Consistent with this result, Cavalieri estimates revealed that AAV2/5-GFP resulted in a significantly larger transduction volume than AAV2/8-GFP (P < 0.05). Each pseudotype transduced striatal neurons effectively [>95% GFP+ cells colocalized neuron-specific nuclear protein (NeuN)]. The current data suggest that AAV2/5 and AAV2/1 are superior to AAV2/8 for gene delivery to the nonhuman primate striatum and therefore better candidates for therapeutic applications targeting this structure.
Dodiya
Hemraj B
HB
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612, USA.
Bjorklund
Tomas
T
Stansell
James
J
Mandel
Ronald J
RJ
Kirik
Deniz
D
Kordower
Jeffrey H
JH
D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism*; D002213:Capsid / Q000378:metabolism*; D000229:Dependovirus / Q000378:metabolism*; D005821:Genetic Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D018613:Microscopy, Confocal / Q000379:methods; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011323:Primates
D049452:Green Fluorescent Proteins