Author + information
- Received February 27, 2019
- Revision received June 20, 2019
- Accepted June 20, 2019
- Published online November 25, 2019.
- Stephen C. Kolwicz Jr., PhDa,
- John K. Hall, PhDb,
- Farid Moussavi-Harami, MDc,
- Xiolan Chen, PhDd,e,
- Stephen D. Hauschka, PhDd,e,
- Jeffrey S. Chamberlain, PhDb,d,e,
- Michael Regnier, PhDe,f,g,∗∗∗ ( and )
- Guy L. Odom, PhDb,e,g,∗∗ ()
- aMitochondria and Metabolism Center, University of Washington, Seattle, Washington
- bDepartment of Neurology, University of Washington, Seattle, Washington
- cDivision of Cardiology, Department of Medicine, University of Washington, Seattle, Washington
- dDepartment of Biochemistry, University of Washington, Seattle, Washington
- eWellstone Muscular Dystrophy Specialized Research Center, University of Washington, Seattle, Washington
- fDepartment of Bioengineering, University of Washington, Seattle, Washington
- gCenter for Cardiovascular Biology, University of Washington, Seattle, Washington
- ↵∗Address for correspondence:
Dr. Guy L. Odom, Department of Neurology, University of Washington, 850 Republican Street, S248, Box 358055, Seattle, Washington 98109.
- ↵∗∗Dr. Michael Regnier, Department of Bioengineering, University of Washington, 850 Republican Street, S180, Seattle, Washington 98109.
• rAAV vectors increase cardiac-specific expression of RNR and elevate cardiomyocyte 2-dATP levels.
• Elevated myocardial RNR and subsequent increase in 2-dATP rescues the performance of failing myocardium, an effect that persists long term.
• We show the ability to increase both cardiac baseline function and high workload contractile performance in aged (22- to 24-month old) mdx4cv mice, by high-level muscle-specific expression of either microdystrophin or RNR.
• Five months post-treatment, mice systemically injected with rAAV6 vector carrying a striated muscle-specific regulatory cassette driving expression of microdystrophin in both skeletal and cardiac muscle, exhibited the greatest effect on systolic function. In comparison, mice treated with rAAV6 vector carrying RNR that expresses exclusively in cardiac muscle not only exhibited greatly improved baseline systolic function but also improved diastolic function.
• Importantly, vector-directed overexpression of RNR did not impair cardiac reserve during increased physiological demand in aged mdx4cv hearts.
Mutations in the gene encoding for dystrophin leads to structural and functional deterioration of cardiomyocytes and is a hallmark of cardiomyopathy in Duchenne muscular dystrophy (DMD) patients. Administration of recombinant adeno-associated viral vectors delivering microdystrophin or ribonucleotide reductase (RNR), under muscle-specific regulatory control, rescues both baseline and high workload-challenged hearts in an aged, DMD mouse model. However, only RNR treatments improved both systolic and diastolic function under those conditions. Cardiac-specific recombinant adeno-associated viral treatment of RNR holds therapeutic promise for improvement of cardiomyopathy in DMD patients.
- diastolic dysfunction
- ribonucleotide reductase
- recombinant adeno-associated virus vectors
↵∗ Drs. Regnier and Odom contributed equally to this work and are joint senior authors.
This work was supported by grants from the National Institutes of Health (NIH): R01 HL111197 (to Dr. Regnier and Hauschka), R01 HD048895, K08 HL128826 (to Dr. Moussavi-Harami) and R01 HL128368 (to Dr. Regnier) and 1U54AR065139-01A1 (to Drs. Hauschka, Chamberlain, Regnier, and Odom). Dr. Kolwicz was funded by the American Heart Association 14SDG18590020. Dr. Chamberlain has received personal fees from Solid Biosciences, SAB. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and US Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received February 27, 2019.
- Revision received June 20, 2019.
- Accepted June 20, 2019.
- 2019 The Authors