Single chain variable fragment antibodies directed against SOD1 ameliorate disease in mutant SOD1 transgenic mice.

Mutations in Cu/Zn superoxide dismutase (SOD1) are the cause of ~20% of cases of familial ALS (FALS), which comprise ~10% of the overall total number of cases of ALS. Mutant (mt) SOD1 is thought to cause FALS through a gain and not loss in function, perhaps as a result of the mutant protein's misfolding and aggregation. Previously we used a phage display library to raise single chain variable fragment antibodies (scFvs) against SOD1, which were found to decrease aggregation of mtSOD1 and toxicity in vitro. In the present study, we show that two scFvs directed against SOD1 ameliorate disease in G93A mtSOD1 transgenic mice and also decrease motor neuron loss, microgliosis, astrocytosis, as well as SOD1 burden and aggregation. The results suggest that the use of antibodies or antibody mimetics directed against SOD1 may be a useful therapeutic direction in mtSOD1-induced FALS. Since studies suggest that wild type SOD1 may be misfolded similar to that seen with mtSOD1, this therapeutic direction may be effective in sporadic as well as FALS.