PMID- 23065925
OWN - NLM
STAT- MEDLINE
DCOM- 20130422
LR  - 20211021
IS  - 1521-2254 (Electronic)
IS  - 1099-498X (Print)
IS  - 1099-498X (Linking)
VI  - 14
IP  - 9-10
DP  - 2012 Sep-Oct
TI  - Adeno-associated virus serotype 9 administered systemically after reperfusion 
      preferentially targets cardiomyocytes in the infarct border zone with 
      pharmacodynamics suitable for the attenuation of left ventricular remodeling.
PG  - 609-20
LID - 10.1002/jgm.2673 [doi]
AB  - BACKGROUND: Adeno-associated virus serotype 9 (AAV9) vectors provide efficient 
      and uniform gene expression to normal myocardium following systemic 
      administration, with kinetics that approach steady-state within 2-3 weeks. 
      However, as a result of the delayed onset of gene expression, AAV vectors have 
      not previously been administered intravenously after reperfusion for post-infarct 
      gene therapy applications. The present study evaluated the therapeutic potential 
      of post-myocardial infarction gene delivery using intravenous AAV9. METHODS: AAV9 
      vectors expressing firefly luciferase, enhanced green fluorescent protein (eGFP) 
      or extracellular superoxide dismutase genes from the cardiac troponin-T (cTnT) 
      promoter (AcTnTLuc, AcTnTeGFP, AcTnTEcSOD) were employed. AcTnTLuc was 
      administered intravenously at 10 min and at 1, 2 and 3 days 
      post-ischemia/reperfusion (IR), and the kinetics of luciferase expression were 
      assessed with bioluminescence imaging. AcTnTeGFP was used to evaluate the 
      distribution of eGFP expression. High-resolution echocardiography was used to 
      evaluate the effects of AcTnTEcSOD on left ventricular (LV) remodeling when 
      injected 10 min post-IR. RESULTS: Compared to sham animals, luciferase expression 
      at 2 days after vector administration was elevated by four-, 24-, 210- and 
      213-fold in groups injected at 10 min, 1 day, 2 days and 3 days post-IR, 
      respectively. The expression of cTnT-driven eGFP was strongest in cardiomyocytes 
      bordering the infarct zone. In the efficacy study of EcSOD, post-infarct LV 
      end-systolic and end-diastolic volumes at days 14 and 28 were significantly 
      smaller in the EcSOD group compared to the control. CONCLUSIONS: Systemic 
      administration of AAV9 vectors after IR both elevates and accelerates gene 
      expression that preferentially targets cardiomyocytes in the border zone with 
      pharmacodynamics suitable for the attenuation of LV remodeling.
CI  - Copyright (c) 2012 John Wiley & Sons, Ltd.
FAU - Konkalmatt, Prasad R
AU  - Konkalmatt PR
AD  - Department of Biomedical Engineering, University of Virginia, Charlottesville, 
      VA, USA.
FAU - Wang, Feng
AU  - Wang F
FAU - Piras, Bryan A
AU  - Piras BA
FAU - Xu, Yaqin
AU  - Xu Y
FAU - O'Connor, Daniel M
AU  - O'Connor DM
FAU - Beyers, Ronald J
AU  - Beyers RJ
FAU - Epstein, Frederick H
AU  - Epstein FH
FAU - Annex, Brian H
AU  - Annex BH
FAU - Hossack, John A
AU  - Hossack JA
FAU - French, Brent A
AU  - French BA
LA  - eng
GR  - R01S HL058582/HL/NHLBI NIH HHS/United States
GR  - S10 RR027333/RR/NCRR NIH HHS/United States
GR  - R01 EB001826/EB/NIBIB NIH HHS/United States
GR  - R01 HL092305/HL/NHLBI NIH HHS/United States
GR  - R01 HL058582/HL/NHLBI NIH HHS/United States
GR  - HL092305/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  - 0 (enhanced green fluorescent protein)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - EC 1.13.12.- (Luciferases)
SB  - IM
MH  - Animals
MH  - Dependovirus/*genetics
MH  - Gene Expression
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors/*administration & dosage/*pharmacokinetics
MH  - Green Fluorescent Proteins/genetics
MH  - Luciferases/genetics
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Myocardial Infarction/genetics/*therapy
MH  - Myocardial Ischemia/genetics/therapy
MH  - *Myocardial Reperfusion
MH  - Myocardial Reperfusion Injury/genetics/therapy
MH  - Myocytes, Cardiac/*drug effects
MH  - Reference Values
MH  - Transgenes
MH  - Ventricular Remodeling/*genetics
PMC - PMC3729029
MID - NIHMS490992
COIS- Conflict of Interest Statement The authors have no disclosures to report relevant 
      to this manuscript.
EDAT- 2012/10/16 06:00
MHDA- 2013/04/23 06:00
PMCR- 2013/09/01
CRDT- 2012/10/16 06:00
PHST- 2012/10/16 06:00 [entrez]
PHST- 2012/10/16 06:00 [pubmed]
PHST- 2013/04/23 06:00 [medline]
PHST- 2013/09/01 00:00 [pmc-release]
AID - 10.1002/jgm.2673 [doi]
PST - ppublish
SO  - J Gene Med. 2012 Sep-Oct;14(9-10):609-20. doi: 10.1002/jgm.2673.