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Differential Transduction Following Basal Ganglia Administration of Distinct Pseudotyped AAV Capsid Serotypes in Nonhuman Primates

Dodiya, Hemraj B.; Björklund, Tomas LU ; Stansell, James, III; Mandel, Ronald J.; Kirik, Deniz LU and Kordower, Jeffrey H. (2010) In Molecular Therapy 18(3). p.579-587
Abstract
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 mu l 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... (More)
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 mu l 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Therapy
volume
18
issue
3
pages
579 - 587
publisher
Nature Publishing Group
external identifiers
  • wos:000275454500017
  • scopus:77649270699
ISSN
1525-0024
DOI
10.1038/mt.2009.216
language
English
LU publication?
yes
id
b35e2f3c-921c-4f40-8472-5a2d2f272175 (old id 1588247)
date added to LUP
2010-04-22 10:05:11
date last changed
2018-06-10 03:08:33
@article{b35e2f3c-921c-4f40-8472-5a2d2f272175,
  abstract     = {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 mu l 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 &lt; 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 &lt; 0.05). Each pseudotype transduced striatal neurons effectively [&gt;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.},
  author       = {Dodiya, Hemraj B. and Björklund, Tomas and Stansell, James, III and Mandel, Ronald J. and Kirik, Deniz and Kordower, Jeffrey H.},
  issn         = {1525-0024},
  language     = {eng},
  number       = {3},
  pages        = {579--587},
  publisher    = {Nature Publishing Group},
  series       = {Molecular Therapy},
  title        = {Differential Transduction Following Basal Ganglia Administration of Distinct Pseudotyped AAV Capsid Serotypes in Nonhuman Primates},
  url          = {http://dx.doi.org/10.1038/mt.2009.216},
  volume       = {18},
  year         = {2010},
}