Research ArticleALS

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

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Science Translational Medicine  05 Dec 2018:
Vol. 10, Issue 470, eaah3924
DOI: 10.1126/scitranslmed.aah3924

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Wellderly antibodies to combat ALS

Amyotrophic lateral sclerosis (ALS) is characterized by the presence of abnormal forms of proteins such as superoxide dismutase 1 (SOD1) that accumulate in neurons, which then degenerate and die. Maier et al. have now developed a human antibody derived from a cohort of healthy elderly individuals that specifically recognizes abnormal SOD1 in postmortem spinal cord tissue from patients with ALS. When administered to animal models of ALS, the antibody delayed the onset of motor impairments, extended the survival of the animals, and reduced the degeneration of neurons and accumulation of SOD1 aggregates. These results support the further evaluation of this human antibody for the potential treatment of ALS involving misfolding of SOD1.

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 SOD1G37R or SOD1G93A 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.

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