TREAT-NEMMYOP

Problem to be solved: No treatment is available for nemaline myopathy (NM), a rare and fatal muscle disease.
Background: A cardinal feature of NM is muscle weakness, caused by atrophy, impaired sarcomere contractility and alterations in energy pathways. This research program builds on our recent in vitro studies, funded by E-RARE1, which suggest that muscle strength in NM might be restored by fast skeletal troponin activation. Preclinical studies with fast skeletal troponin activators in live NM mice are now warranted.
Objective: Determine the efficacy of the fast skeletal troponin activator tirasemtiv in live NM mice.
Approach: Tirasemtiv will be tested in four NM mouse models: this allows us to cover a large spectrum of the disease. We will study its effect on muscle function, energy metabolism and NM biomarkers using non-invasive magnetic resonance imaging and spectroscopy, measurements of in vivo and ex vivo muscle strength and proteomic assessments of the involved signaling pathways. This combination allows for an in-depth analysis of the efficacy of tirasemtiv in NM mice
Innovation: The availability of (1) four NM mouse models, (2) high-end infrastructure to assess muscle – and whole body performance, and (3) a novel and promising drug, positions us ideally to tackle the problem posed.
Impact: Our research program is positioned at the level of basic science and its translation towards direct clinical application; its outcome might provide an impetus to preclinical studies in other disorders with muscle weakness.