PMID- 21487395
OWN - NLM
STAT- MEDLINE
DCOM- 20110930
LR  - 20211020
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 19
IP  - 6
DP  - 2011 Jun
TI  - Preclinical differences of intravascular AAV9 delivery to neurons and glia: a 
      comparative study of adult mice and nonhuman primates.
PG  - 1058-69
LID - 10.1038/mt.2011.72 [doi]
AB  - Other labs have previously reported the ability of adeno-associated virus 
      serotype 9 (AAV9) to cross the blood-brain barrier (BBB). In this report, we 
      carefully characterized variables that might affect AAV9's efficiency for central 
      nervous system (CNS) transduction in adult mice, including dose, vehicle 
      composition, mannitol coadministration, and use of single-stranded versus 
      self-complementary AAV. We report that AAV9 is able to transduce approximately 
      twice as many neurons as astrocytes across the entire extent of the adult rodent 
      CNS at doses of 1.25 x 10(1)(2), 1 x 10(1)(3), and 8 x 10(1)(3) vg/kg. Vehicle composition or 
      mannitol coadministration had only modest effects on CNS transduction, suggesting 
      AAV9 crosses the BBB by an active transport mechanism. Self-complementary vectors 
      were greater than tenfold more efficient than single-stranded vectors. When this 
      approach was applied to juvenile nonhuman primates (NHPs) at the middle dose 
      (9-9.5 x 10(1)(2) vg/kg) tested in mice, a reduction in peripheral organ and brain 
      transduction was observed compared to mice, along with a clear shift toward 
      mostly glial transduction. Moreover, the presence of low levels of pre-existing 
      neutralizing antibodies (NAbs) mostly occluded CNS and peripheral transduction 
      using this delivery approach. Our results indicate that high peripheral tropism, 
      limited neuronal transduction in NHPs, and pre-existing NAbs represent 
      significant barriers to human translation of intravascular AAV9 delivery.
FAU - Gray, Steven J
AU  - Gray SJ
AD  - Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, 
      North Carolina, USA. graysj@email.unc.edu
FAU - Matagne, Valerie
AU  - Matagne V
FAU - Bachaboina, Lavanya
AU  - Bachaboina L
FAU - Yadav, Swati
AU  - Yadav S
FAU - Ojeda, Sergio R
AU  - Ojeda SR
FAU - Samulski, R Jude
AU  - Samulski RJ
LA  - eng
GR  - P51 RR000163-51/RR/NCRR NIH HHS/United States
GR  - U54 AR056953/AR/NIAMS NIH HHS/United States
GR  - P51 RR000163/RR/NCRR NIH HHS/United States
GR  - U54-AR056953/AR/NIAMS NIH HHS/United States
GR  - K01 RR000163/RR/NCRR NIH HHS/United States
GR  - RR000163/RR/NCRR NIH HHS/United States
GR  - U54 AR056953-01/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110412
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
SB  - IM
CIN - Mol Ther. 2011 Jun;19(6):1006-7. PMID: 21629257
MH  - Animals
MH  - Dependovirus/*genetics
MH  - Female
MH  - Genetic Vectors/*genetics
MH  - HEK293 Cells
MH  - HeLa Cells
MH  - Humans
MH  - Macaca mulatta
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Neuroglia/*metabolism
MH  - Neurons/*metabolism
MH  - Polymerase Chain Reaction
MH  - Primates
PMC - PMC3129805
EDAT- 2011/04/14 06:00
MHDA- 2011/10/01 06:00
PMCR- 2012/06/01
CRDT- 2011/04/14 06:00
PHST- 2011/04/14 06:00 [entrez]
PHST- 2011/04/14 06:00 [pubmed]
PHST- 2011/10/01 06:00 [medline]
PHST- 2012/06/01 00:00 [pmc-release]
AID - S1525-0016(16)31910-4 [pii]
AID - 10.1038/mt.2011.72 [doi]
PST - ppublish
SO  - Mol Ther. 2011 Jun;19(6):1058-69. doi: 10.1038/mt.2011.72. Epub 2011 Apr 12.