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

Publication

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

Journal Paper/Review - Dec 5, 2018

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

Citation

Maier M, Nitsch R, Christoph H, Weber M, Perrin S, Stehle T, Späni C, Kulic L, Vieira F, McAfoose J, Preisig D, Montrasio F, Wirth F, Welt T, 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)

Journal

Sci Transl Med 2018; 10

Publication Date

Dec 5, 2018

Issn Electronic

1946-6242

Brief description/objective

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.