Construction of a model for myositis based on human disease

Summary of research

Myositis is an auto-immune disease affecting around 250.000 people in Europe. Patients suffer from severe muscle weakness and inflammation, heavily impacting their daily activities and quality of life. Up to half of the patients develop pulmonary and cardiac conditions due to chronic multi-organ inflammation. The need for improved, patient-centered therapies is evident as current treatment strategies are insufficient, cause side effects and require intensive intramural care. 

A better understanding of the pathophysiology underlying muscle weakness is key to identify contributors that should be targeted to prevent or revert this defect in an early stage. Myositis specific autoantibodies (MSA) and the complement system cause direct muscle damage, but patients also show impaired muscle fiber contraction with unknown cause. Based on pilot data revealing reduced muscle fiber contractility in myositis patients with MSA, a two-step approach is proposed to determine the impact of MSA and complement on muscle contractility:

1. Analysis of human muscle fiber contractility from biopsies of patients with MSA and treatment effects of standard of care immunosuppressant therapy.
2. Establishment of an ex vivo model of mouse muscle fiber contractility, a unique read-out for myositis based on muscular function. It enables screening for patient MSA that impair muscle fiber contractility and proprietary compounds that restore this. 

The consortium combines the necessary expertise on myositis (AmsterdamUMC-AMC), muscle physiology (AmsterdamUMC-VUMC) assays and compounds (Argenx) to successfully establish an innovative model that closely resembles the human condition, which enables testing of novel proprietary compounds (Argenx). 

The project will generate unique insights in the interplay between the immune system and muscle fiber contractility. Proof-of-concept of a negative impact of MSA and complement on muscle contractility will empower first-in-human studies (Argenx) of tailored immunotherapy not only for myositis patients but also for patients with other immune mediated conditions involving muscle weakness (e.g. ICU-weakness, vasculitis).

Awarded grant, amount: €667.000,-

Funding agency: TKI