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.
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.
Authors: Christina A Pacak; Cathryn S Mah; Bijoy D Thattaliyath; Thomas J Conlon; Melissa A Lewis; Denise E Cloutier; Irene Zolotukhin; Alice F Tarantal; Barry J Byrne Journal: Circ Res Date: 2006-07-27 Impact factor: 17.367
Authors: Katsuya Inagaki; Sally Fuess; Theresa A Storm; Gregory A Gibson; Charles F Mctiernan; Mark A Kay; Hiroyuki Nakai Journal: Mol Ther Date: 2006-05-19 Impact factor: 11.454
Authors: Patrick A Helm; Peter Caravan; Brent A French; Vincent Jacques; Luhua Shen; Yaqin Xu; Ronald J Beyers; R Jack Roy; Christopher M Kramer; Frederick H Epstein Journal: Radiology Date: 2008-04-10 Impact factor: 11.105
Authors: Jarrod A Call; Kristopher H Chain; Kyle S Martin; Vitor A Lira; Mitsuharu Okutsu; Mei Zhang; Zhen Yan Journal: Circ Heart Fail Date: 2014-12-11 Impact factor: 8.790
Authors: Jinliang Li; Shannon C Kelly; Jan R Ivey; Pamela K Thorne; Kelly P Yamada; Tadao Aikawa; Renata Mazurek; James R Turk; Kleiton Augusto Santos Silva; Amira R Amin; Darla L Tharp; Christina M Mueller; Hrishikesh Thakur; Emily V Leary; Timothy L Domeier; R Scott Rector; Kenneth Fish; Federico Cividini; Kiyotake Ishikawa; Craig A Emter; Michael S Kapiloff Journal: Physiol Genomics Date: 2022-06-01 Impact factor: 4.297
Authors: Eliana C Martinez; Jinliang Li; Jennifer Arthur Ataam; Kristin Tokarski; Hrishikesh Thakur; Ioannis Karakikes; Kimberly Dodge-Kafka; Michael S Kapiloff Journal: Gene Ther Date: 2022-02-01 Impact factor: 4.184
Authors: Daniel M O'Connor; Nivedita K Naresh; Bryan A Piras; Yaqin Xu; Robert S Smith; Frederick H Epstein; John A Hossack; Roy C Ogle; Brent A French Journal: Physiol Rep Date: 2015-03