Targeted immunotherapy for amyotrophic lateral sclerosis and frontotemporal dementia abstract frontotemporal dementias (FTD) and amyotrophic lateral sclerosis (ALS) are progressive and fatal…

Targeted immunotherapy for amyotrophic lateral sclerosis and frontotemporal dementia abstract frontotemporal dementias (FTD) and amyotrophic lateral sclerosis (ALS) are progressive and fatal neurodegenerative diseases. A hexanucleotide repeat expansion in C9ORF72 accounts for >10% of all cases. Non-AUG dependent translation of expanded repeats results in accumulation of several dipeptide repeat (DPR) proteins, of which poly-GA appears central to the pathology of C9ORF72 disease. Aggregation of poly-GA inhibits the proteasome and leads to TDP-43 aggregation. Despite widespread poly-GA expression in C9ORF72 mouse models, specific disease-relevant neuron populations are especially sensitive to poly-GA toxicity. Antisense oligonucleotides directed to C9ORF72 are effective in mice, as is a dominant negative protein kinase R (PKR) that attenuates poly-GA accumulation. Preliminary data indicate that active vaccination induces high antibody titers and nearly complete prevention of motor deficits and microglia activation in mice, suggesting poly-GA as a feasible target to treat C9ORF72 FTD/ALS. Poly-GA antibodies block aggregation and spreading of poly-GA and attenuate downstream TDP-43 pathology in vitro, and improve motor and behavioral deficits in mouse models. These data suggest that immunotherapy is currently the best approach to reduce toxicity of aggregates that are found even in pre-symptomatic carriers. Our team has identified potent murine antibodies that demonstrate activity in a C9ORF72 mouse model. During this phase 1 study, we propose to humanize our lead anti-GA antibody and conduct preclinical validation of anti-GA antibody therapy in several disease-relevant mouse models.