Kantonsspital St.Gallen
login

A human-derived antibody targets misfolded SOD1 and ameliorates motor symptoms in mouse models of amyotrophic lateral sclerosis

Marcel Maier, Tobias Welt, Fabian Wirth, Fabio Montrasio, Daniel Preisig, Jordan McAfoose, Fernando G Vieira, Luka Kulic, Claudia Späni, Thilo Stehle, Steve Perrin, Markus Weber, Christoph Hock, Roger M Nitsch & Jan Grimm

abstract Mutations in the gene encoding superoxide dismutase 1 (SOD1) lead to misfolding and aggregation of SOD1 and cause familial amyotrophic lateral sclerosis (FALS). However, the implications of wild-type SOD1 misfolding in sporadic forms of ALS (SALS) remain unclear. By screening human memory B cells from a large cohort of healthy elderly subjects, we generated a recombinant human monoclonal antibody (α-miSOD1) that selectively bound to misfolded SOD1, but not to physiological SOD1 dimers. On postmortem spinal cord sections from 121 patients with ALS, α-miSOD1 antibody identified misfolded SOD1 in a majority of cases, regardless of their SOD1 genotype. In contrast, the α-miSOD1 antibody did not bind to its epitope in most of the 41 postmortem spinal cord sections from non-neurological control (NNC) patients. In transgenic mice overexpressing disease-causing human SOD1 or SOD1 mutations, treatment with the α-miSOD1 antibody delayed the onset of motor symptoms, extended survival by up to 2 months, and reduced aggregation of misfolded SOD1 and motor neuron degeneration. These effects were obtained whether α-miSOD1 antibody treatment was administered by direct brain infusion or peripheral administration. These results support the further development of α-miSOD1 antibody as a candidate treatment for ALS involving misfolding of SOD1.
   
citation Maier M, Welt T, Wirth F, Montrasio F, Preisig D, McAfoose J, Vieira F G, Kulic L, Späni C, Stehle T, Perrin S, Weber M, Hock C, Nitsch R M, Grimm J. A human-derived antibody targets misfolded SOD1 and ameliorates motor symptoms in mouse models of amyotrophic lateral sclerosis. Sci Transl Med 2018; 10:.
   
type journal paper/review (English)
date of publishing 05-12-2018
journal title Sci Transl Med (10/470)
ISSN electronic 1946-6242
PubMed 30518612
DOI 10.1126/scitranslmed.aah3924