Fast Skeletal Troponin Activation for Restoring Muscle Strength in Mouse Models of Nemaline Myopathy: a Molecular, Cellular, Metabolic and Functional Assessment – TREAT-NEMMYOP

Nemaline myopathy (NM) is a rare and fatal neuromuscular disorder with an estimated
prevalence of 1 in 50.000 live births. The main clinical feature of NM is muscle weakness,
which impairs swallowing and causes severe respiratory problems. In children suffering from
NM, the diaphragm is often severely affected, leading to suffocation. There is currently no
treatment for NM, and efforts are directed at alleviating symptoms and compensating for
disabilities as far as possible. Our E-Rare 1 project NEMMYOP has yielded important
results on (1) the pathophysiology of muscle weakness in NM, on (2) new NM biomarkers,
and on (3) in vitro effects of troponin activators on muscle fibres of NM patients. The insights
gained in NEMMYOP have provided the first indications for a possible treatment for NM.
To build upon this promising finding, TREAT-NEMMYOP will determine the efficacy of
tirasemtiv, a fast skeletal troponin activator, in four NM mouse models. TREATNEMMYOP
will make the next pivotal step towards clinical trials and future treatment
of NM.
To reach our aim, TREAT-NEMMYOP will assess the effect of tirasemtiv on (i) muscle
function, (ii) energy metabolism and (iii) NM biomarkers. To obtain an in-depth evaluation of
tirasemtiv efficacy, we will combine measurements of in vivo and ex vivo muscle strength,
non-invasive magnetic resonance imaging (MRI) and spectroscopy with analysis of the
involved signalling pathways and proteome. This also enables us to better understand the
pathology of NM and the molecular mechanisms by which compounds such as tirasemtiv
increase muscle strength in NM patients.
TREAT-NEMMYOP is a powerful consortium of three academic groups and complementary
collaborative partners, including the developer of tirasemtiv (Cytokinetics Inc.). The
consortium has access to four unique NM mouse models and a high-end infrastructure that
enables thorough assessment of muscle- and whole body performance. This makes
TREAT-NEMMYOP well equipped to assess the efficacy of this highly promising treatment
option for NM.