Grant: Operating Grant - Priority Announcement: ALS Canada Research Fund

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by the progressive degeneration of motor neurons. Here we propose to develop antibody-derived proteins (nanobodies) that will bind new therapeutic targets for ALS. The first part of the project aims to derive a nanobody-based therapy to reduce the burden of pathogenic misfolded superoxide dismutase proteins in the nervous system. We will compare the therapeutic effects of different methods for viral delivery of nanobodies in transgenic ALS mice overexpressing mutant SOD1. The second part aims to develop a nanobody-based therapy for TDP-43-mediated pathogenesis. TDP-43 aggregates are a hallmark of ALS and we recently proposed a pathogenic pathway based on the interaction of TDP-43 with the p65 subunit of nuclear factor kappa B, a key component of inflammatory responses. Viral vectors encoding nanobodies to block TDP-43 binding to p65 NF-kB will be tested in transgenic mice overexpressing mutant TDP-43 which develop pathological hallmarks of human ALS.