G.P.13.03 Can VLA-4 be applied as a biomarker for prognosis and therapeutic target in Duchenne muscular dystrophy?

Abstract

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy, affecting about 1 in 3500 male births, caused by mutations or deletions in the dystrophin gene. Even though the primary genetic mutation causes a modification in the resistance of the muscle fibers to damage, studies in animal models as well as in DMD patients have strongly suggested that the immune response observed in this disease could also contribute to the progressive fibrosis and fat infiltration observed in the muscles. The molecular mechanisms that could be involved in this intense migration of immune cells into the damaged muscle have not yet been established. We have followed a cohort of 49 boys with DMD which was subdivided according to the severity of the disease. Each group was studied for the expression of the integrin-type extracellular matrix (ECM) receptors on the surface of the T cells obtained from the blood, as well as for the ECM-driven migratory response of these T cells in vitro. In addition the inflammatory infiltrate in the muscle tissue of DMD patients has been characterized. We observed a positive correlation between the percentage of T cells expressing high levels of the fibronectin receptor in CD4+ T cells in the blood according to the severity of the disease. In addition, the relative numbers of VLA-4hi T cells was positively correlated with a more rapid evolution and therefore a more severe outcome. We have also demonstrated that the mononuclear cells obtained from patients either with a poor prognosis or in an advanced phase of the disease had a higher fibronectin-driven migratory response when compared with mildly affected patients and with control individuals. Importantly, this process could be blocked by pre-treatment with an anti-VLA-4 monoclonal antibody. Thus, we propose that VLA-4 can be considered a target molecule for prognosis and its blockage as a possible therapeutic option in DMD.