PMID- 18720429
OWN - NLM
STAT- MEDLINE
DCOM- 20081216
LR  - 20211020
IS  - 1521-2254 (Electronic)
IS  - 1099-498X (Print)
IS  - 1099-498X (Linking)
VI  - 10
IP  - 10
DP  - 2008 Oct
TI  - Recombinant adeno-associated virus-mediated gene delivery of long chain acyl 
      coenzyme A dehydrogenase (LCAD) into LCAD-deficient mice.
PG  - 1113-23
LID - 10.1002/jgm.1242 [doi]
AB  - BACKGROUND: Very long chain acyl coenzyme A (CoA) dehydrogenase (VLCAD) 
      deficiency is a relatively common mitochondrial beta-oxidation disorder. The most 
      severe form of VLCAD deficiency presents with neonatal cardiomyopathy and hepatic 
      failure and is generally fatal within the first year of life. Mice deficient for 
      long chain acyl CoA dehydrogenase (LCAD) closely resemble the clinical syndrome 
      observed in VLCAD-deficient humans. Recombinant adeno-associated viral (rAAV) 
      vectors with pseudotype capsids were investigated for their potential towards 
      correcting the phenotype observed in mice heterozygous (+/-) for LCAD (i.e. liver 
      and muscle steatosis). METHODS: rAAV containing the mouse LCAD cDNA (mLCAD) under 
      the transcriptional control of the CMV/chicken beta-actin hybrid promoter were 
      injected intramuscularly into the tibialis anterior (TA) muscle of LCAD(+/-) mice 
      or injected into the portal vein to transduce hepatocytes. RESULTS: Ten weeks 
      post-injection of rAAV1-mLCAD into the TA muscle, significantly increased levels 
      of mLCAD within mitochondria were demonstrated by immunostaining of TA sections, 
      immunoblotting of mitochondrial isolates and by the electron transfer 
      flavoprotein (ETF) fluorescence reduction enzyme activity assay. Magnetic 
      resonance spectroscopy of vector-injected TA muscle demonstrated a reduction in 
      the lipid content compared to phosphate-buffered saline-injected mice, whereas a 
      systemic effect was observed as a reduction in liver macrosteatosis. Eight weeks 
      after portal vein injection of rAAV8-mLCAD into LCAD(+/-) mice, increased levels 
      of mLCAD within hepatocyte mitochondria were demonstrated by immunostaining and 
      also by the ETF assay. Scoring of the hepatosteatosis observed in partially 
      deficient LCAD mice indicated a reduction in the lipid content within livers of 
      vector-treated mice. CONCLUSIONS: These studies show that rAAV-mediated delivery 
      of mLCAD was efficient and led to an amelioration of local and systemic 
      pathologies observed in partially deficient LCAD mice.
CI  - Copyright (c) 2008 John Wiley & Sons, Ltd.
FAU - Beattie, Stuart G
AU  - Beattie SG
AD  - University of Massachusetts Medical School, Worcester, MA 01655, USA.
FAU - Goetzman, Eric
AU  - Goetzman E
FAU - Tang, Qiuishi
AU  - Tang Q
FAU - Conlon, Thomas
AU  - Conlon T
FAU - Campbell-Thompson, Martha
AU  - Campbell-Thompson M
FAU - Matern, Dietrich
AU  - Matern D
FAU - Vockley, Jerry
AU  - Vockley J
FAU - Flotte, Terence R
AU  - Flotte TR
LA  - eng
GR  - P01 HL059412/HL/NHLBI NIH HHS/United States
GR  - P50 HL059412/HL/NHLBI NIH HHS/United States
GR  - R01 DK078775/DK/NIDDK NIH HHS/United States
GR  - HL-59412/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - England
TA  - J Gene Med
JT  - The journal of gene medicine
JID - 9815764
RN  - EC 1.3.8.8 (Acyl-CoA Dehydrogenase, Long-Chain)
SB  - IM
MH  - Acyl-CoA Dehydrogenase, Long-Chain/*deficiency/*genetics/metabolism
MH  - Animals
MH  - Dependovirus/*genetics/metabolism
MH  - Female
MH  - Gene Transfer Techniques
MH  - *Genetic Vectors/administration & dosage
MH  - Liver/metabolism
MH  - Male
MH  - Mice
MH  - Transduction, Genetic
PMC - PMC4319113
MID - NIHMS659081
EDAT- 2008/08/23 09:00
MHDA- 2008/12/17 09:00
PMCR- 2015/02/06
CRDT- 2008/08/23 09:00
PHST- 2008/08/23 09:00 [pubmed]
PHST- 2008/12/17 09:00 [medline]
PHST- 2008/08/23 09:00 [entrez]
PHST- 2015/02/06 00:00 [pmc-release]
AID - 10.1002/jgm.1242 [doi]
PST - ppublish
SO  - J Gene Med. 2008 Oct;10(10):1113-23. doi: 10.1002/jgm.1242.