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

Neuron. 2020 Feb 19;105(4):645-662.e11. doi: 10.1016/j.neuron.2019.11.007. Epub 2019 Dec 9.


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.

Keywords: BAC transgenic mice; C9orf72 ALS/FTD; G4C2 repeat expansion; RAN proteins; human antibody; immunotherapy; microsatellite expansion; proteasome and autophagy; protein co-aggregation; repeat associated non-ATG (RAN) translation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / genetics*
  • Antibodies, Monoclonal / metabolism
  • Brain / metabolism
  • C9orf72 Protein / genetics*
  • C9orf72 Protein / metabolism
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Frontotemporal Dementia / genetics*
  • Frontotemporal Dementia / metabolism
  • Gene Targeting / methods
  • Genetic Therapy / methods*
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phenotype
  • Random Allocation
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • ran GTP-Binding Protein / antagonists & inhibitors
  • ran GTP-Binding Protein / metabolism*


  • Antibodies, Monoclonal
  • C9orf72 Protein
  • C9orf72 protein, mouse
  • Ran protein, mouse
  • Recombinant Proteins
  • ran GTP-Binding Protein