title: Ribonucleotide reductase-mediated increase in dATP improves cardiac performance via myosin activation in a large animal model of heart failure.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pathology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.|Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine University of Washington, Seattle, WA, USA.
authors: Shin
authors: S
authors: Kadota
authors: North American Science Associates Inc., Northwood, OH, USA.
authors: John
authors: J
authors: Carey
authors: Department of Pathology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.|Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine University of Washington, Seattle, WA, USA.
authors: Hans
authors: H
authors: Reinecke
authors: BEAT Biotherapeutics Corp., Seattle, WA, USA.
authors: James
authors: J
authors: Leggett
authors: BEAT Biotherapeutics Corp., Seattle, WA, USA.
authors: Sam
authors: S
authors: Teichman
authors: Department of Pathology, Institute for Stem Cell and Regenerative Medicine, 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 A
authors: MA
authors: Laflamme
authors: Department of Pathology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.|Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine University of Washington, Seattle, WA, USA.|Department of Bioengineering University of Washington, Seattle, WA, USA.|Department of Medicine/Cardiology, University of Washington, Seattle, WA, USA.
authors: Charles E
authors: CE
authors: Murry
authors: Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine University of Washington, Seattle, WA, USA.|Department of Bioengineering University of Washington, Seattle, WA, USA.
authors: Michael
authors: M
authors: Regnier
authors: BEAT Biotherapeutics Corp., Seattle, WA, USA.
authors: Gregory G
authors: GG
authors: Mahairas
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002908:Chronic Disease; D003838:Deoxyadenine Nucleotides / Q000032:analysis*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004452:Echocardiography; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006333:Heart Failure / Q000503:physiopathology / Q000628:therapy*; D006352:Heart Ventricles / Q000187:drug effects; D006439:Hemodynamics; D006801:Humans; D009203:Myocardial Infarction / Q000150:complications; D010865:Pilot Projects; D012264:Ribonucleotide Reductases / Q000494:pharmacology*; D013552:Swine; D013556:Swine, Miniature; D013599:Systole / Q000187:drug effects
chemical_list: D003838:Deoxyadenine Nucleotides; D012264:Ribonucleotide Reductases; C026600:2'-deoxyadenosine triphosphate
keywords: 2-deoxy-ATP; Gene therapy; Heart failure; Ribonucleotide reductase