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Eur J Heart Fail. 2015 Aug;17(8):772-81. doi: 10.1002/ejhf.270. Epub 2015 Apr 15.

Ribonucleotide reductase-mediated increase in dATP improves cardiac performance via myosin activation in a large animal model of heart failure.

Author information

1
Department of Pathology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
2
Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine University of Washington, Seattle, WA, USA.
3
North American Science Associates Inc., Northwood, OH, USA.
4
BEAT Biotherapeutics Corp., Seattle, WA, USA.
5
Department of Bioengineering University of Washington, Seattle, WA, USA.
6
Department of Medicine/Cardiology, University of Washington, Seattle, WA, USA.

Abstract

AIMS:

Heart failure remains a leading cause of morbidity, hospitalizations, and deaths. We previously showed that overexpression of the enzyme ribonucleotide reductase (RNR) in cardiomyocytes increased levels of the myosin activator, 2-deoxy-ATP, catalysed enhanced contraction, and improved cardiac performance in rodent hearts. Here we used a swine model of myocardial infarction (MI) to test preliminarily a novel gene therapy for heart failure based on delivery of the human RNR enzyme complex under the control of a cardiac-specific promoter via an adeno-associated virus serotype 6 vector--designated as BB-R12.

METHODS AND RESULTS:

We induced heart failure following MI in Yucatan minipigs by balloon occlusion of the left anterior descending artery. Two weeks, later, pigs received BB-R12 at one of three doses via antegrade coronary infusion. At 2 months post-treatment, LVEF and systolic LV dimension (measured by echocardiography) improved significantly in the high-dose group, despite further deterioration in the saline controls. Haemodynamic parameters including LV end-diastolic pressure, +dP/dt, and -dP/dt all trended towards improvement in the high-dose group. We observed no difference in the histopathological appearance of hearts or other organs from treated animals vs. controls, nor did we encounter any safety or tolerability concerns following BB-R12 delivery.

CONCLUSION:

These pilot results suggest cardiac-specific gene therapy using BB-R12 may reverse cardiac dysfunction by myosin activation in a large-animal heart failure model with no observed safety concerns. Thus further research into the therapeutic potential of BB-R12 for patients with chronic heart failure appears warranted.

KEYWORDS:

2-deoxy-ATP; Gene therapy; Heart failure; Ribonucleotide reductase

Comment in

PMID:
25876005
PMCID:
PMC5523878
DOI:
10.1002/ejhf.270
[Indexed for MEDLINE]
Free PMC Article

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