Improving Cardiorespiratory Performance in DMD via Combinatorial Dystrophin and Ribonucleotide Reductase Gene Therapy
Abstract
Dystrophin provides a structural link between the inside and outside of muscle cells to protect against damage during exercise. Duchenne muscular dystrophy (DMD) patients carrying mutations to the dystrophin gene gradually lose muscle function and ultimately die due to weakened heart and breathing muscles. Two current limitations of DMD cardiac gene therapy include: (1) overcoming the preexisting damage to muscles caused by disease progression that ultimately leads to cardiomyopathy-or worse (heart failure) and (2) the inability to restore lost function of those muscle cells that express a highly truncated dystrophin protein (i.e., microdystrophin, currently advancing in clinical trials). These challenges limit the effective response of strategies for sustained protective therapy. To address these concerns, we propose a two-pronged approach: dystrophin replacement (structural-based therapy) coupled with contractile performance enhancement via ribonucleotide reductase (RNR) expression (contractile augmentation therapy). Our group has shown that elevation of the end product of RNR, 2 deoxy-ATP (dATP), increases the strength and kinetics of contractile performance in infarcted rat and pig hearts. More recently, we obtained exciting preliminary data that this same treatment improves cardiac performance of deteriorating or aged (22- to 24-month-old) hearts of dmd mice and that improved performance was sustained long term. Interestingly, systemic treatment of aged dmd mice with RNR vectors resulted in not only improved cardiac systolic (contractile) performance, but also rescued several parameters of diastolic (relaxation) performance. Cardiac muscle lacks the ability to regenerate, so endowing existing cardiomyocytes that actively contribute to rhythmic contractions with the ability for sustained increases in force production (via elevated RNR and dATP) represents a mechanistic-based therapy at the level of the muscle contractile unit (sarcomere) that increases whole heart function. We have demonstrated that the contractile protein myosin can utilize dATP as a preferred energy that results in stronger, faster heart muscle cell contraction as well as faster relaxation to improve whole heart function for both systole and diastole. This RNR strategy may be even more effective when combined with dystrophin replacement strategies to improve the stability of muscle cell structure. Our proposal is clearly focused on bringing successful cardiac gene therapies for DMD into clinical application in the next 3-5 years with the goal of making a significant clinical impact. Importantly, our proposed studies will demonstrate major benefits for the entire DMD patient community, as the strategy is potentially applicable to all DMD patients irrespective of the type of dystrophin mutation or stage of disease progression.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810624
Entities
People
- Guy Odom
Organizations
- United States Army
- University of Washington