Skip to main content
SpringerLink
Log in

Cardiac Myosin Activation with Gene Therapy Produces Sustained Inotropic Effects and May Treat Heart Failure with Reduced Ejection Fraction

  • Chapter
  • First Online:
Heart Failure

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 243))

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 219.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 279.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 379.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AAV6-R1:

Single AAV6 vector expressing R1 subunit

AAV6-R1.2:

Single AAV6 vector expressing R1 & R2 subunits, linked by P2a

AAV6-R2:

Single AAV6 vector expressing R2 subunit

AV-R1:

Single AV vector expressing R1 subunit

AV-R2:

Single AV vector expressing R2 subunit

BB-R12:

AAV6 viral vector with a cardiac-specific promoter cTnT455 to overexpress R1R2 in the heart

dATP:

2-Deoxy-adenosine triphosphate

HF:

Heart failure

R1:

Rrm1 subunit of ribonucleotide reductase

R1R2:

Ribonucleotide reductase

R2:

Rrm2 subunit of ribonucleotide reductase

TgRR:

Transgenic mouse model overexpressing R1R2

References

  • Ahmad MF, Dealwis CG (2013) The structural basis for the allosteric regulation of ribonucleotide reductase. Prog Mol Biol Transl Sci 117:389–410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ambardekar AV, Buttrick PM (2011) Reverse remodeling with left ventricular assist devices: a review of clinical, cellular, and molecular effects. Circ Heart Fail 4(2):224–233

    Article  PubMed  PubMed Central  Google Scholar 

  • Arnett AL, Beutler LR, Quintana A et al (2013) Heparin-binding correlates with increased efficiency of AAV1- and AAV6-mediated transduction of striated muscle, but negatively impacts CNS transduction. Gene Ther 20(5):497–503

    Article  CAS  PubMed  Google Scholar 

  • Baker AJ (2011) Refueling the heart: using 2-deoxy-ATP to enhance cardiac contractility. J Mol Cell Cardiol 51(6):883–884

    Article  CAS  PubMed  Google Scholar 

  • Caras IW, Martin DW (1988) Molecular cloning of the cDNA for a mutant mouse ribonucleotide reductase M1 that produces a dominant mutator phenotype in mammalian cells. Mol Cell Biol 8(7):2698–2704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng Y, Hogarth KA, O'Sullivan ML, Regnier M, Pyle WG (2016) 2-Deoxyadenosine triphosphate restores the contractile function of cardiac myofibril from adult dogs with naturally occurring dilated cardiomyopathy. Am J Physiol Heart Circ Physiol 310(1):H80–H91

    Article  PubMed  Google Scholar 

  • Cleland JG, Teerlink JR, Senior R et al (2011) The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet 378(9792):676–683

    Article  CAS  PubMed  Google Scholar 

  • Cohn JN, Goldstein SO, Greenberg BH et al (1998) A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. Vesnarinone Trial Investigators. N Engl J Med 339(25):1810–1816

    Article  CAS  PubMed  Google Scholar 

  • Dixon JA, Spinale FG (2009) Large animal models of heart failure: a critical link in the translation of basic science to clinical practice. Circ Heart Fail 2(3):262–271

    Article  PubMed  PubMed Central  Google Scholar 

  • Feest ER, Steven Korte F, Tu AY et al (2014) Thin filament incorporation of an engineered cardiac troponin C variant (L48Q) enhances contractility in intact cardiomyocytes from healthy and infarcted hearts. J Mol Cell Cardiol 72:219–227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Francis GS, Bartos JA, Adatya S (2014) Inotropes. J Am Coll Cardiol 63(20):2069–2078

    Article  PubMed  Google Scholar 

  • Gao G, Bish LT, Sleeper MM et al (2011) Transendocardial delivery of AAV6 results in highly efficient and global cardiac gene transfer in rhesus macaques. Hum Gene Ther 22(8):979–984

    Article  CAS  PubMed  Google Scholar 

  • Greenberg BH, Chou W, Saikali KG et al (2015) Safety and tolerability of omecamtiv mecarbil during exercise in patients with ischemic cardiomyopathy and angina. JACC Heart Fail 3(1):22–29

    Article  PubMed  Google Scholar 

  • Ishikawa K, Tilemann L, Ladage D et al (2012) Cardiac gene therapy in large animals: bridge from bench to bedside. Gene Ther 19(6):670–677

    Article  CAS  PubMed  Google Scholar 

  • Kadota S, Carey J, Reinecke H et al (2015) Ribonucleotide reductase-mediated increase in dATP improves cardiac performance via myosin activation in a large animal model of heart failure. Eur J Heart Fail 17(8):772–781

    Article  CAS  PubMed  Google Scholar 

  • Kolwicz SC, Odom GL, Nowakowski SG et al (2016) AAV6-mediated cardiac-specific overexpression of ribonucleotide reductase enhances myocardial contractility. Mol Ther 24:240–250

    Article  CAS  PubMed  Google Scholar 

  • Korte FS, Dai J, Buckley K et al (2011) Upregulation of cardiomyocyte ribonucleotide reductase increases intracellular 2 deoxy-ATP, contractility, and relaxation. J Mol Cell Cardiol 51(6):894–901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lowes BD, Higginbotham M, Petrovich L et al (2000) Low-dose enoximone improves exercise capacity in chronic heart failure. Enoximone Study Group. J Am Coll Cardiol 36(2):501–508

    Article  CAS  PubMed  Google Scholar 

  • Lundy SD, Murphy SA, Dupras SK et al (2014) Cell-based delivery of dATP via gap junctions enhances cardiac contractility. J Mol Cell Cardiol 72:350–359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lüscher TF (2014) Heart failure: the epidemic of the new century. Eur Heart J 35(48):3389–3390

    Article  PubMed  Google Scholar 

  • Malik FI, Hartman JJ, Elias KA et al (2011) Cardiac myosin activation: a potential therapeutic approach for systolic heart failure. Science 331(6023):1439–1443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moussavi-Harami F, Razumova MV, Racca AW, Cheng Y, Stempien-Otero A, Regnier M (2015) 2-Deoxy adenosine triphosphate improves contraction in human end-stage heart failure. J Mol Cell Cardiol 79:256–263

    Article  CAS  PubMed  Google Scholar 

  • Nowakowski S, Adamek N, Geeves M et al (2013) 2-Deoxy-ATP alters myosin structure to enhance cross-bridge cycling and improve cardiac function [Abstract]. Presented at Biophysical Society 57th Annual Meeting, 2–6 February 2013, Philadelphia, PA2013

    Google Scholar 

  • Nowakowski SG, Kolwicz SC, Korte FS et al (2013b) Transgenic overexpression of ribonucleotide reductase improves cardiac performance. Proc Natl Acad Sci U S A 110(15):6187–6192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Palomeque J, Chemaly ER, Colosi P et al (2007) Efficiency of eight different AAV serotypes in transducing rat myocardium in vivo. Gene Ther 14(13):989–997

    Article  CAS  PubMed  Google Scholar 

  • Pleger ST, Brinks H, Ritterhoff J et al (2013) Heart failure gene therapy: the path to clinical practice. Circ Res 113(6):792–809

    Article  CAS  PubMed  Google Scholar 

  • Redfield MM (2002) Heart failure—an epidemic of uncertain proportions. N Engl J Med 347(18):1442–1444

    Article  PubMed  Google Scholar 

  • Regnier M, Homsher E (1998) The effect of ATP analogs on posthydrolytic and force development steps in skinned skeletal muscle fibers. Biophys J 74(6):3059–3071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Regnier M, Lee DM, Homsher E (1998a) ATP analogs and muscle contraction: mechanics and kinetics of nucleoside triphosphate binding and hydrolysis. Biophys J 74(6):3044–3058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Regnier M, Martyn DA, Chase PB (1998b) Calcium regulation of tension redevelopment kinetics with 2-deoxy-ATP or low [ATP] in rabbit skeletal muscle. Biophys J 74(4):2005–2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Regnier M, Rivera AJ, Chen Y, Chase PB (2000) 2-deoxy-ATP enhances contractility of rat cardiac muscle. Circ Res 86(12):1211–1217

    Article  CAS  PubMed  Google Scholar 

  • Regnier M, Martin H, Barsotti RJ, Rivera AJ, Martyn DA, Clemmens E (2004) Cross-bridge versus thin filament contributions to the level and rate of force development in cardiac muscle. Biophys J 87(3):1815–1824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schoffstall B, Chase PB (2008) Increased intracellular [dATP] enhances cardiac contraction in embryonic chick cardiomyocytes. J Cell Biochem 104(6):2217–2227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schoffstall B, Clark A, Chase PB (2006) Positive inotropic effects of low dATP/ATP ratios on mechanics and kinetics of porcine cardiac muscle. Biophys J 91(6):2216–2226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Solomon SD, Foster E, Bourgoun M et al (2010) Effect of cardiac resynchronization therapy on reverse remodeling and relation to outcome: multicenter automatic defibrillator implantation trial: cardiac resynchronization therapy. Circulation 122(10):985–992

    Article  PubMed  Google Scholar 

  • Teerlink JR (2009) A novel approach to improve cardiac performance: cardiac myosin activators. Heart Fail Rev 14(4):289–298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Teerlink JR, Felker GM, McMurry JJV et al (2016) Acute treatment with omecamtiv mecarbil to increase contractility in acute heart failure. The ATOMIC-AHF Study. J Am Coll Cardiol 67:1444–1455

    Article  CAS  PubMed  Google Scholar 

  • Tilemann L, Ishikawa K, Weber T, Hajjar RJ (2012) Gene therapy for heart failure. Circ Res 110(5):777–793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yancy CW, Jessup M, Bozkurt B et al (2013) 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 62(16):e147–e239

    Article  PubMed  Google Scholar 

Download references

Disclosures

MR is a scientific founder and equity holder in BEAT Biotherapeutics Corp. SLT is an employee of BEAT Biotherapeutics Corp.

Sources of Funding

Work in MR’s laboratory was supported by NIH grants R01 HL061683, R01 HL065497, R01 HL111197, and R21 HL091368.

Author information

Authors and Affiliations

  1. BEAT Biotherapeutics Corp, 1380 112th Ave., NE, Suite 200, Seattle, WA, 98004, USA

    Sam L. Teichman

  2. Department of Bioengineering, University of Washington, Seattle, WA, USA

    Kassandra S. Thomson & Michael Regnier

  3. Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA

    Michael Regnier

Authors
  1. Sam L. Teichman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kassandra S. Thomson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Regnier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sam L. Teichman .

Editor information

Editors and Affiliations

  1. Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover Klinik für Kardiologie und Angiologie, Hannover, Niedersachsen, Germany

    Johann Bauersachs

  2. Heart Institute, Stony Brook University , Stony Brook, New York, USA

    Javed Butler

  3. Heart and Lung Diseases, Bayer Pharma Aktiengesellschaft Heart and Lung Diseases, Wuppertal, Nordrhein-Westfalen, Germany

    Peter Sandner

Rights and permissions

Reprints and permissions

Copyright information

© 2016 SpringerInternationalPublishingSwitzerland

About this chapter

Cite this chapter

Teichman, S.L., Thomson, K.S., Regnier, M. (2016). Cardiac Myosin Activation with Gene Therapy Produces Sustained Inotropic Effects and May Treat Heart Failure with Reduced Ejection Fraction. In: Bauersachs, J., Butler, J., Sandner, P. (eds) Heart Failure. Handbook of Experimental Pharmacology, vol 243. Springer, Cham. https://doi.org/10.1007/164_2016_31

Download citation

Publish with us

Policies and ethics

Search

Navigation