PMID- 18701909
OWN - NLM
STAT- MEDLINE
DCOM- 20090706
LR  - 20211020
IS  - 1476-5462 (Electronic)
IS  - 0969-7128 (Print)
IS  - 0969-7128 (Linking)
VI  - 16
IP  - 1
DP  - 2009 Jan
TI  - Enhancing transduction of the liver by adeno-associated viral vectors.
PG  - 60-9
LID - 10.1038/gt.2008.137 [doi]
AB  - A number of distinct factors acting at different stages of the adeno-associated 
      virus vector (AAV)-mediated gene transfer process were found to influence murine 
      hepatocyte transduction. Foremost among these was the viral capsid protein. 
      Self-complementary (sc) AAV pseudotyped with capsid from serotype 8 or rh.10 
      mediated fourfold greater hepatocyte transduction for a given vector dose when 
      compared with vector packaged with AAV7 capsid. An almost linear relationship 
      between vector dose and transgene expression was noted for all serotypes with 
      vector doses as low as 1 x 10(7) vg per mouse (4 x 10(8) vg kg(-1)) mediating 
      therapeutic levels of human FIX (hFIX) expression. Gender significantly 
      influenced scAAV-mediated transgene expression, with twofold higher levels of 
      expression observed in male compared with female mice. Pretreatment of mice with 
      the proteasome inhibitor bortezomib increased scAAV-mediated hFIX expression from 
      4+/-0.6 to 9+/-2 microg ml(-1) in female mice, although the effect of this agent 
      was less profound in males. Exposure of mice to adenovirus 10-20 weeks after gene 
      transfer with AAV vectors augmented AAV transgene expression twofold by 
      increasing the level of proviral mRNA. Hence, optimization of individual steps in 
      the AAV gene transfer process can further enhance the potency of AAV-mediated 
      transgene expression, thus increasing the probability of successful gene therapy.
FAU - Nathwani, A C
AU  - Nathwani AC
AD  - Department of Haematology, UCL Cancer Institute, London, UK. a.nathwani@ucl.ac.uk
FAU - Cochrane, M
AU  - Cochrane M
FAU - McIntosh, J
AU  - McIntosh J
FAU - Ng, C Y C
AU  - Ng CY
FAU - Zhou, J
AU  - Zhou J
FAU - Gray, J T
AU  - Gray JT
FAU - Davidoff, A M
AU  - Davidoff AM
LA  - eng
GR  - R01 HL073838-04/HL/NHLBI NIH HHS/United States
GR  - DH_/Department of Health/United Kingdom
GR  - G0502121/MRC_/Medical Research Council/United Kingdom
GR  - HL073838/HL/NHLBI NIH HHS/United States
GR  - R01 HL073838/HL/NHLBI NIH HHS/United States
GR  - R01 HL094396/HL/NHLBI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20080814
PL  - England
TA  - Gene Ther
JT  - Gene therapy
JID - 9421525
RN  - 0 (Antibodies, Viral)
RN  - 0 (Boronic Acids)
RN  - 0 (Protease Inhibitors)
RN  - 0 (Pyrazines)
RN  - 0 (factor IX Long Beach)
RN  - 69G8BD63PP (Bortezomib)
RN  - 9001-28-9 (Factor IX)
SB  - IM
MH  - Animals
MH  - Antibodies, Viral/analysis
MH  - Boronic Acids/pharmacology
MH  - Bortezomib
MH  - Dependovirus/*genetics/immunology/metabolism
MH  - Factor IX/genetics/metabolism
MH  - Female
MH  - Gene Expression
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors/*administration & dosage/genetics/immunology
MH  - Humans
MH  - Injections, Intravenous
MH  - Liver/immunology/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Protease Inhibitors/pharmacology
MH  - Pyrazines/pharmacology
MH  - Transduction, Genetic/*methods
MH  - Transgenes
PMC - PMC2615795
MID - NIHMS71333
EDAT- 2008/08/15 09:00
MHDA- 2009/07/07 09:00
PMCR- 2009/07/01
CRDT- 2008/08/15 09:00
PHST- 2008/08/15 09:00 [pubmed]
PHST- 2009/07/07 09:00 [medline]
PHST- 2008/08/15 09:00 [entrez]
PHST- 2009/07/01 00:00 [pmc-release]
AID - gt2008137 [pii]
AID - 10.1038/gt.2008.137 [doi]
PST - ppublish
SO  - Gene Ther. 2009 Jan;16(1):60-9. doi: 10.1038/gt.2008.137. Epub 2008 Aug 14.