title: Cardiac Myosin Activation with Gene Therapy Produces Sustained Inotropic Effects and May Treat Heart Failure with Reduced Ejection Fraction.
abstract: Chronic inotropic therapy is effective for the treatment of heart failure with reduced ejection fraction, but has been limited by adverse long-term safety profiles, development of tolerance, and the need for chronic parenteral administration. A safe and convenient therapeutic agent that produces sustained inotropic effects could improve symptoms, functional capacity, and quality of life. Small amounts of 2-deoxy-adenosine triphosphate (dATP) activate cardiac myosin leading to enhanced contractility in normal and failing heart muscle. Cardiac myosin activation triggers faster myosin crossbridge cycling with greater force generation during each contraction. This paper describes the rationale and results of a translational medicine effort to increase dATP levels using a gene therapy strategy to deliver and upregulate ribonucleotide reductase (R1R2), the enzyme responsible for dATP synthesis, selectively in cardiomyocytes. In small and large animal models of heart failure, a single dose of this gene therapy has led to sustained inotropic effects with a benign safety profile. Further animal studies are appropriate with the goal of testing this agent in patients with heart failure.
authors: BEAT Biotherapeutics Corp, 1380 112th Ave., NE, Suite 200, Seattle, WA, 98004, USA. steichman@beatbiotherapeutics.com.
authors: Sam L
authors: SL
authors: Teichman
authors: Department of Bioengineering, University of Washington, Seattle, WA, USA.
authors: Kassandra S
authors: KS
authors: Thomson
authors: Department of Bioengineering, University of Washington, Seattle, WA, USA.|Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
authors: Michael
authors: M
authors: Regnier
mesh_terms: D000818:Animals; D024722:Cardiac Myosins / Q000235:genetics*; D003838:Deoxyadenine Nucleotides / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D009200:Myocardial Contraction / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism*; D013318:Stroke Volume
chemical_list: D003838:Deoxyadenine Nucleotides; D024722:Cardiac Myosins; C026600:2'-deoxyadenosine triphosphate
keywords: Cardiac myosin activation; Gene therapy; Heart failure; Inotropic therapy; Ribonucleotide reductase; Translational medicine; dATP