title: Cardiac I-1c overexpression with reengineered AAV improves cardiac function in swine ischemic heart failure.
abstract: Cardiac gene therapy has emerged as a promising option to treat advanced heart failure (HF). Advances in molecular biology and gene targeting approaches are offering further novel options for genetic manipulation of the cardiovascular system. The aim of this study was to improve cardiac function in chronic HF by overexpressing constitutively active inhibitor-1 (I-1c) using a novel cardiotropic vector generated by capsid reengineering of adeno-associated virus (BNP116). One month after a large anterior myocardial infarction, 20 Yorkshire pigs randomly received intracoronary injection of either high-dose BNP116.I-1c (1.0 × 10(13) vector genomes (vg), n = 7), low-dose BNP116.I-1c (3.0 × 10(12) vg, n = 7), or saline (n = 6). Compared to baseline, mean left ventricular ejection fraction increased by 5.7% in the high-dose group, and by 5.2% in the low-dose group, whereas it decreased by 7% in the saline group. Additionally, preload-recruitable stroke work obtained from pressure-volume analysis demonstrated significantly higher cardiac performance in the high-dose group. Likewise, other hemodynamic parameters, including stroke volume and contractility index indicated improved cardiac function after the I-1c gene transfer. Furthermore, BNP116 showed a favorable gene expression pattern for targeting the heart. In summary, I-1c overexpression using BNP116 improves cardiac function in a clinically relevant model of ischemic HF.
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Kiyotake
authors.initials: K
authors.lastname: Ishikawa
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Fish
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Tilemann
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Kleopatra
authors.initials: K
authors.lastname: Rapti
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Jaume
authors.initials: J
authors.lastname: Aguero
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Santos-Gallego
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Ahyoung
authors.initials: A
authors.lastname: Lee
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Karakikes
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Chaoqin
authors.initials: C
authors.lastname: Xie
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Fadi G
authors.initials: FG
authors.lastname: Akar
authors.affiliation: Department of Medicine, Beth Israel Medical Center, University Hospital and Manhattan Campus for the Albert Einstein College of Medicine, New York, New York, USA.
authors.forename: Yuichi J
authors.initials: YJ
authors.lastname: Shimada
authors.affiliation: Gwathmey Inc., Cambridge, Massachusetts, USA.
authors.forename: Judith K
authors.initials: JK
authors.lastname: Gwathmey
authors.affiliation: Gene Therapy Center, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Aravind
authors.initials: A
authors.lastname: Asokan
authors.affiliation: Asklepios BioPharmaceutical, Chapel Hill, NC.
authors.forename: Scott
authors.initials: S
authors.lastname: McPhee
authors.affiliation: Asklepios BioPharmaceutical, Chapel Hill, NC.
authors.forename: Jade
authors.initials: J
authors.lastname: Samulski
authors.affiliation: Gene Therapy Center, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Richard Jude
authors.initials: RJ
authors.lastname: Samulski
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Sigg
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Weber
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Evangelia G
authors.initials: EG
authors.lastname: Kranias
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address: roger.hajjar@mssm.edu.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000145:classification / Q000201:enzymology / Q000235:genetics*; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D006333:Heart Failure / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D007269:Injections, Intra-Arterial; D009203:Myocardial Infarction / Q000503:physiopathology* / Q000628:therapy*; D054645:Protein Phosphatase 1 / Q000235:genetics* / Q000378:metabolism; D013318:Stroke Volume; D013552:Swine
chemical_list: D054645:Protein Phosphatase 1