Improving Cardiorespiratory Performance in DMD via Combinatorial Dystrophin and Ribonucleotide Reductase Gene Therapy
Abstract
Duchenne muscular dystrophy (DMD) is caused by mutations in the gene encoding dystrophin, a structural protein that links the cytoplasmic contractile components of muscle cells to the extracellular matrix. Our dual target research strategy mediated by recombinant adeno-associated viral vectors (rAAV) utilizes dystrophin replacement (structural-based therapy) coupled with contractile performance enhancement via ribonucleotide reductase (RNR) expression (contractile augmentation therapy)). Therefore, we will address the underlying DMD structural deficit (lack of dystrophin), protecting muscle cells from further injury, while simultaneously improving cardiac muscle contractility and relaxation via a promising new nucleotide therapy. We recently published data (see appendix) demonstrating rAAV/RNR treatment improves cardiac performance of deteriorating or aged (22-24 month-old) hearts of dmd mice, and that improved performance was sustained long-term. In fulfillment of Aim-1 for this grant, following vector production/ purification (Oct-Nov, 2018), dmd mice were administered rAAVs (Dec-Jan 2018/19). Echocardiography has been performed on the majority of treated mice with end points forthcoming on the final 2-cohorts of animals over the coming weeks (Nov. 2019). End points for the 4-cohorts of treated mice for Aim-1/Phase-1 are currently in process (Oct-Nov 2019) where we have performed cardiac perfusion assays (baseline performance, pressure-volume relationships, and high-workload performance) in ~60 of the mice at the time of writing this report.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2020
- Accession Number
- AD1129174
Entities
People
- Guy L. Odom
Organizations
- Seattle University