PMID- 21811247
OWN - NLM
STAT- MEDLINE
DCOM- 20120305
LR  - 20211020
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 19
IP  - 11
DP  - 2011 Nov
TI  - Systemic gene delivery in large species for targeting spinal cord, brain, and 
      peripheral tissues for pediatric disorders.
PG  - 1971-80
LID - 10.1038/mt.2011.157 [doi]
AB  - Adeno-associated virus type 9 (AAV9) is a powerful tool for delivering genes 
      throughout the central nervous system (CNS) following intravenous injection. 
      Preclinical results in pediatric models of spinal muscular atrophy (SMA) and 
      lysosomal storage disorders provide a compelling case for advancing AAV9 to the 
      clinic. An important translational step is to demonstrate efficient CNS targeting 
      in large animals at various ages. In the present study, we tested systemically 
      injected AAV9 in cynomolgus macaques, administered at birth through 3 years of 
      age for targeting CNS and peripheral tissues. We show that AAV9 was efficient at 
      crossing the blood-brain barrier (BBB) at all time points investigated. Transgene 
      expression was detected primarily in glial cells throughout the brain, dorsal 
      root ganglia neurons and motor neurons within the spinal cord, providing 
      confidence for translation to SMA patients. Systemic injection also efficiently 
      targeted skeletal muscle and peripheral organs. To specifically target the CNS, 
      we explored AAV9 delivery to cerebrospinal fluid (CSF). CSF injection efficiently 
      targeted motor neurons, and restricted gene expression to the CNS, providing an 
      alternate delivery route and potentially lower manufacturing requirements for 
      older, larger patients. Our findings support the use of AAV9 for gene transfer to 
      the CNS for disorders in pediatric populations.
FAU - Bevan, Adam K
AU  - Bevan AK
AD  - Center for Gene Therapy, The Research Institute at Nationwide Children's 
      Hospital, Columbus, Ohio 43205, USA.
FAU - Duque, Sandra
AU  - Duque S
FAU - Foust, Kevin D
AU  - Foust KD
FAU - Morales, Pablo R
AU  - Morales PR
FAU - Braun, Lyndsey
AU  - Braun L
FAU - Schmelzer, Leah
AU  - Schmelzer L
FAU - Chan, Curtis M
AU  - Chan CM
FAU - McCrate, Mary
AU  - McCrate M
FAU - Chicoine, Louis G
AU  - Chicoine LG
FAU - Coley, Brian D
AU  - Coley BD
FAU - Porensky, Paul N
AU  - Porensky PN
FAU - Kolb, Stephen J
AU  - Kolb SJ
FAU - Mendell, Jerry R
AU  - Mendell JR
FAU - Burghes, Arthur H M
AU  - Burghes AH
FAU - Kaspar, Brian K
AU  - Kaspar BK
LA  - eng
GR  - K08 NS067282/NS/NINDS NIH HHS/United States
GR  - R21 NS064328/NS/NINDS NIH HHS/United States
GR  - RC2 NS069476/NS/NINDS NIH HHS/United States
GR  - RC2 NS69476-01/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110802
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
SB  - IM
MH  - Animals
MH  - Brain/metabolism
MH  - Dependovirus/genetics
MH  - Gene Expression Regulation
MH  - *Gene Transfer Techniques
MH  - *Genetic Therapy
MH  - Genetic Vectors/administration & dosage/genetics
MH  - HEK293 Cells
MH  - Humans
MH  - Injections, Epidural
MH  - Injections, Intra-Arterial
MH  - Macaca
MH  - Male
MH  - Motor Neurons/metabolism
MH  - Muscle, Skeletal/metabolism
MH  - Muscular Atrophy, Spinal/genetics/*therapy
MH  - Neuroglia/metabolism
MH  - Spinal Cord/metabolism
MH  - Swine
MH  - Time Factors
MH  - Transduction, Genetic
MH  - Transgenes/genetics
PMC - PMC3222525
EDAT- 2011/08/04 06:00
MHDA- 2012/03/06 06:00
PMCR- 2011/11/01
CRDT- 2011/08/04 06:00
PHST- 2011/08/04 06:00 [entrez]
PHST- 2011/08/04 06:00 [pubmed]
PHST- 2012/03/06 06:00 [medline]
PHST- 2011/11/01 00:00 [pmc-release]
AID - S1525-0016(16)32794-0 [pii]
AID - 10.1038/mt.2011.157 [doi]
PST - ppublish
SO  - Mol Ther. 2011 Nov;19(11):1971-80. doi: 10.1038/mt.2011.157. Epub 2011 Aug 2.