Development of a novel remyelination-based strategy in MS-patients: assembly and validation of a modified anti-sulfatide antibody capable of inducing (re)myelination independently of environmental cues
03 / 2005 - 03 / 2009
Stichting MS Research
Multiple sclerosis (MS) is the most well-known demyelinating disease, but its main cause is still unknown, while an effective therapy is not yet available. Although current treatments are aimed at preventing demyelination, remyelination-based therapies are necessary to repair the existing demyelinated axons. In this regard, significant numbers of oligodendrocyte progenitor cells have indeed been identified in chronic MS lesions. However, the cells appear to be quiescent and fail to expand and differentiate, probably due to a lack of appropriate signalling factors for progenitors to respond to. To overcome this environmental restriction, we recently initiated detailed investigations of an approach that relies on antibody-induced remyelination. Antibodies against certain transmembrane 'receptors' can mimic the receptor's ligand by similarly causing activation of given signalling molecules, as occurs upon receptor-ligand interaction. For this reason antibodies may represent valuable tools as modulators of cell behaviour, thereby obviating addition of soluble ligands or cell-cell/cell-ECM-dependent signal activators. In the CNS, antibody-mediated remyelination as well as de(dys)myelination occurs upon injection of anti-sulfatide antibodies. This apparent discrepancy can however readily be explained by taking into account the presence of the ECM, since in vitro anti-sulfatide antibodies inhibit myelin sheet formation on a laminin-2 substrate, whereas myelination is induced on fibronectin (Baron et al., manuscript in preparation). In fact, these data imply an important role for the ECM in directing anti-sulfatide-mediated myelination. The present project outlines a research program, which is aimed at clarifying the role of the ECM in regulating antibody-induced remyelination. To this end, we will obtain insight into the mechanism of action of sulfatide (and anti-sulfatide antibodies) on ECM-dependent myelination. In addition, we will develop and evaluate the effects of RGD-conjugated anti-sulfatide antibodies. The rationale for developing RGD-conjugated anti-sulfatide antibodies is that in principle they should engage simultaneously with sulfatide and fibronectin receptors (?v integrins), thereby directing oligodendrocyte myelination, independently of other environmental cues. We anticipate that the proposed experiments will pave the way for an antibody-mediated manipulation of oligodendrocyte behaviour, representing a potential powerful approach to directly enhance and/or improve remyelination, effectively linking fundamental research and clinical application. Keywords: myelination, sulfatide/GalCer, membrane microdomains, antibody, extracellular matrix.