Antibody therapy targeting RAN proteins rescues C9 ALS/FTD phenotypes in C9orf72 mouse model

SUMMARY:

The intronic C9orf72 G4C2 expansion, the most common genetic cause of ALS and FTD, produces sense- and antisense-expansion RNAs and six dipeptide repeat-associated, non-ATG (RAN) proteins, but their roles in disease are unclear. We generated high-affinity human antibodies targeting GA or GP RAN proteins. These antibodies cross the blood-brain barrier and co-localize with intracellular RAN aggregates in C9-ALS/FTD BAC mice. In cells, α-GA ₁ interacts with TRIM21 and α-GA ₁ treatment reduced GA levels, increased GA turnover, decreased RAN toxicity and decreased co-aggregation of proteasome and autophagy proteins to GA aggregates. In C9-BAC mice, α-GA ₁ reduced GA as well as GP and GR proteins, improved behavioral deficits, decreased neuroinflammation and neurodegeneration, and increased survival. Glycosylation of the Fc region of α-GA ₁ is important for cell entry and efficacy. These data demonstrate RAN proteins drive C9-ALS/FTD in C9-BAC transgenic mice and establish a novel therapeutic approach for C9orf72 ALS/FTD and other RAN-protein diseases.