PMID- 21386820
OWN - NLM
STAT- MEDLINE
DCOM- 20110930
LR  - 20220309
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 19
IP  - 6
DP  - 2011 Jun
TI  - Correction of neurological disease of mucopolysaccharidosis IIIB in adult mice by 
      rAAV9 trans-blood-brain barrier gene delivery.
PG  - 1025-33
LID - 10.1038/mt.2011.34 [doi]
AB  - The greatest challenge in developing therapies for mucopolysaccharidosis (MPS) 
      IIIB is to achieve efficient central nervous system (CNS) delivery across the 
      blood-brain barrier (BBB). In this study, we used the novel ability of 
      adeno-associated virus serotype 9 (AAV9) to cross the BBB from the vasculature to 
      achieve long-term global CNS, and widespread somatic restoration of 
      alpha-N-acetylglucosaminidase (NAGLU) activity. A single intravenous (IV) injection 
      of rAAV9-CMV-hNAGLU, without extraneous treatment to disrupt the BBB, restored 
      NAGLU activity to normal or above normal levels in adult MPS IIIB mice, leading 
      to the correction of lysosomal storage pathology in the CNS and periphery, and 
      correction of astrocytosis and neurodegeneration. The IV delivered rAAV9 vector 
      also transduced abundant neurons in the myenteric and submucosal plexus, 
      suggesting peripheral nervous system (PNS) targeting. While CNS entry did not 
      depend on osmotic disruption of the BBB, it was significantly enhanced by 
      pretreatment with an IV infusion of mannitol. Most important, we demonstrate that 
      a single systemic rAAV9-NAGLU gene delivery provides long-term (>18 months) 
      neurological benefits in MPS IIIB mice, resulting in significant improvement in 
      behavioral performance, and extension of survival. These data suggest promising 
      clinical potential using the trans-BBB neurotropic rAAV9 vector for treating MPS 
      IIIB and other neurogenetic diseases.
FAU - Fu, Haiyan
AU  - Fu H
AD  - The Center for Gene Therapy, The Research Institute at Nationwide Children's 
      Hospital, Columbus, Ohio 43205, USA.
FAU - Dirosario, Julianne
AU  - Dirosario J
FAU - Killedar, Smruti
AU  - Killedar S
FAU - Zaraspe, Kimberly
AU  - Zaraspe K
FAU - McCarty, Douglas M
AU  - McCarty DM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110308
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - EC 3.2.1.50 (alpha-N-acetyl-D-glucosaminidase)
RN  - EC 3.2.1.52 (Acetylglucosaminidase)
SB  - IM
MH  - Acetylglucosaminidase/genetics/*metabolism
MH  - Animals
MH  - Blood-Brain Barrier/*metabolism
MH  - Dependovirus/*genetics
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors/*genetics
MH  - Mice
MH  - Mice, Knockout
MH  - Mucopolysaccharidosis III/*therapy
MH  - Nervous System Diseases/*therapy
MH  - Polymerase Chain Reaction
PMC - PMC3129800
EDAT- 2011/03/10 06:00
MHDA- 2011/10/01 06:00
PMCR- 2012/06/01
CRDT- 2011/03/10 06:00
PHST- 2011/03/10 06:00 [entrez]
PHST- 2011/03/10 06:00 [pubmed]
PHST- 2011/10/01 06:00 [medline]
PHST- 2012/06/01 00:00 [pmc-release]
AID - S1525-0016(16)31906-2 [pii]
AID - 10.1038/mt.2011.34 [doi]
PST - ppublish
SO  - Mol Ther. 2011 Jun;19(6):1025-33. doi: 10.1038/mt.2011.34. Epub 2011 Mar 8.