Highlights from the first day at the World Muscle Society meeting in Mendoza, Argentina, provided by CureDuchnne’s scientist, Dr. Mike Kelly.
It’s recognized that Duchenne and Becker muscular dystrophy carrier-mothers are at high risk for developing various dystrophic complications. Recent studies suggest that the incidence of cardiac and non-cardiac manifestations occurs earlier (and with higher frequency) than previously thought.
Megan Iammarino (Center for Gene Therapy at Nationwide Children’s Hospital) reported on their recent work to characterize the skeletal and cardiac muscle of Duchenne and Becker muscular dystrophy carrier-mothers compared to healthy controls. They found creatine kinase (CK) levels were significantly elevated in the majority of carrier-mothers, and almost half of the somatic carrier-mothers had cardiomyopathy as measured by MRI late gadolinium enhancement (measuring cardiac fibrosis).
In a separated poster from the same group (Center for Gene Therapy at Nationwide Children’s Hospital), Linda Cripe reported (Duchenne and Becker Muscular Dystrophy Carriers: Emerging Evidence for a Clinically Important Cardiomyopathy) on a longitudinal prospective study to define the incidence of cardiac disease in mothers of males with Duchenne and Becker muscular dystrophy. The results were similar to that reported above, and emphasized the risk of developing cardiomyopathy. Through MRI, carrier-mothers were shown to develop cardiac fibrosis prior to the onset of abnormal cardiac function, and demonstrated an increased frequency of premature ventricular contractions during exercise.
Taken together, these reports underline the importance of awareness and regular examinations for carrier-mothers, as well as the need to initiate early-stage treatment options.
Dimitry Vlodavets (Russian Children’s Neuromuscular Center, Moscow) reported recent developments of their micro-utrophin mini gene therapy and the therapeutic benefit seen upon administration to the mdx/utr double-knockout mice (a more severe mouse model of Duchenne). Three different micro-utrophin sequences were prepared (Murine, Human and Human codon-optimized) and each was delivered both intramuscularly and intravenously using AAV9. All three micro-utrophins were expressed in skeletal muscles as well as heart. Strength was significantly improved in the treated mice, especially with the codon-optimized human sequence. This work lays the foundation for further studies leading to human clinical trials with micro-utrophin gene therapy.
Russell Rodgers (Smidt Heart Institute, Cedars-Sinai Medical Center) described the therapeutic benefit of intravenous cardiac progenitor cells (and exosomes) in the mdx mouse model of Duchenne. A single IV infusion of either mouse Cardiosphere-derived Cells (CDC) or human CDC-derived exosomes improved both cardiac and skeletal muscle function in the mdx mouse. Functional improvements were associated with regression of muscle pathology – reduced fibrosis and inflammation along with augmented regeneration. This work strongly supports the ongoing HOPE-2 DMD trial examining the effect of IV administration of human CDCs in Duchenne patients. The trial is actively recruiting Duchenne patients.