#apaperaday: Modulating fast skeletal muscle contraction protects skeletal muscle in animal models of Duchenne muscular dystrophy
In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Modulating fast skeletal muscle contraction protects skeletal muscle in animal models of Duchenne muscular dystrophy
We kick off with a preclinical study by Russell et al on EDG-5506 in Journal of Clinical Investigation. Doi 10.1172/JCI153837. EDG-5506 is the compound developed by Edgewise Therapeutics for Duchenne and Becker. Duchenne is caused by lack of dystrophin. Note that muscle fibers do not need dystrophin to contract, but that without dystrophin, fibers are prone to be damaged by contracting.
Muscle fibers come in two flavors: slow (endurance) and fast (strength). The fast fibers are prone to damage from contractions. Authors wanted to explore an approach targeting specifically the fast fibers.
They did a screening for compounds reducing ATP hydrolysis of fast myosin. Myosin is the main protein involved in contraction. Fast & slow fibers have different types of myosin. Preventing ATP hydrolysis for fast myosin makes its connection to muscle fiber skeleton (actin) < strong.
This will result in a muscle fiber that is less strong BUT that does not hurt itself contracting. Authors showed EDG-5506 was specific for fast fibers, and did not affect heart or smooth muscles (that express different myosins).
They also showed that EDG-5506 only affects fast and not slow fibers within a muscle. In mdx mice (no dystrophin) EDG-5506 treatment resulted in less damage and less force drop after an eccentric contraction in different settings (ex vivo, in situ and in animal).
The force of treated mice was slightly reduced before exercise but the force drop was reduced more (so less loss of strength due to contraction injury). Treated dystrophic mice and dogs were more active but has less CK (so less muscle damage). Also in mdx mouse there was less uptake of evan’s blue dye (less muscle damage) and less fibrosis in diaphragm and d2/mdx tibialis anterior. What is nice to see is that authors match specific questions to specific models that are optimal to answer each question.
My only question is whether this translates fully to the human situation. Mice have 90% fast fibers, humans a lot less. As such the therapeutic effect may be larger in mice than patients. However the force drop due to treatment is probably also less in humans. Clinical trials in healthy volunteers and Becker patients have been completed. Longer term studies are ongoing in Duchenne and Becker patients now with EDG-5506 (with oral delivery!)
I think the approach is interesting and I hope the compound is effective and safe in Duchenne and Becker. However we will need to wait for the trial results to draw conclusions. Commend the authors for the very diligent preclinical studies and sharing this with the community.
