Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model.

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-GA1 interacts with TRIM21, and α-GA1 treatment reduced GA levels, increased GA turnover, and decreased RAN toxicity and co-aggregation of proteasome and autophagy proteins to GA aggregates. In C9-BAC mice, α-GA1 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-GA1 is important for cell entry and efficacy. These data demonstrate that 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. Copyright © 2019 Elsevier Inc. All rights reserved.

Citation

Lien Nguyen, Fabio Montrasio, Amrutha Pattamatta, Solaleh Khoramian Tusi, Olgert Bardhi, Kevin D Meyer, Lindsey Hayes, Katsuya Nakamura, Monica Banez-Coronel, Alyssa Coyne, Shu Guo, Lauren A Laboissonniere, Yuanzheng Gu, Saravanakumar Narayanan, Benjamin Smith, Roger M Nitsch, Mark W Kankel, Mia Rushe, Jeffrey Rothstein, Tao Zu, Jan Grimm, Laura P W Ranum. Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model. Neuron. 2020 Feb 19;105(4):645-662.e11

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PMID: 31831332

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