Mutations in the gene SOD1 can cause the enzyme it encodes to fold in ways that are harmful to neurons—an abnormality that’s responsible for about 20% of familial amyotrophic lateral sclerosis (ALS). Scientists led by the Swiss biotech Neurimmune have designed a recombinant human monoclonal antibody that could selectively bind to misfolded SOD1, and they’ve turned up positive preclinical results that they say support further development of the drug candidate.
The Neurimmune-led team hypothesized that the misfolding of SOD1 triggers immune responses that leave behind memory B cells. After screening a library of memory B cells from healthy elderly people for reactivity against misfolded SOD1, they generated a recombinant antibody called α-miSOD1. The antibody binds specifically to misfolded SOD1 but leaves normal enzymes alone, the team reported in the journal Science Translational Medicine.
Recent studies have generated strong evidence that SOD1 misfolding and aggregation leads to some forms of ALS. A team at the Umeå University in Sweden, for example, observed a templated spread of SOD1 pathology in mice and suggested that drugs targeting the aggregates offer a way to tackle the disease.
That’s exactly what α-miSOD1 is meant to do. First, the researchers found that the antibody targets misfolded SOD1 in motor neurons on postmortem spinal cord samples from both familial and sporadic ALS patients, while none or only weak immune activity was observed in samples from control individuals.
What’s more important, the team also reported encouraging results from three transgenic mouse models that over-express disease-causing human SOD1 mutations. After treatment with α-miSOD1 through direct injection into the brain or through abdomen, the rodents experienced reductions in both the aggregation of misfolded SOD1 and nerve cell degeneration, as well as improvements in movement symptoms. Survival was extended by up to two months, according to the team.
Neurimmune has been focusing on disorders in the central nervous system for some time and it’s perhaps most well known for a collaboration with Biogen. The partnership encompasses such drugs as Alzheimer’s candidate aducanumab, which was generated using the same technology as the company applied to the α-miSOD1 antibody.
Biogen and partner Ionis are also developing an ALS drug targeting SOD1. Dubbed BIIB067, the DNA-based therapy extended survival in mice and rats and has entered human studies.
Now with the positive in-mice results, the Neurimmune candidate drug deserves further development as a potential treatment for patients with ALS marked by misfolded SOD1, said the researchers in the study.