Virus-mediated delivery of antibody targeting TAR DNA-binding protein-43 mitigates associated neuropathology

J Clin Invest. 2019 Feb 25;129(4):1581-1595. doi: 10.1172/JCI123931.

Abstract

The cytoplasmic aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of degenerating neurons in amyotrophic lateral sclerosis (ALS) and subsets of frontotemporal dementia (FTD). In order to reduce TDP-43 pathology, we generated single-chain (scFv) antibodies against the RNA recognition motif 1 (RRM1) of TDP-43, which is involved in abnormal protein self-aggregation and interaction with p65 NF-κB. Virus-mediated delivery into the nervous system of a scFv antibody, named VH7Vk9, reduced microgliosis in a mouse model of acute neuroinflammation and mitigated cognitive impairment, motor defects, TDP-43 proteinopathy, and neuroinflammation in transgenic mice expressing ALS-linked TDP-43 mutations. These results suggest that antibodies targeting the RRM1 domain of TDP-43 might provide new therapeutic avenues for the treatment of ALS and FTD.

Keywords: Immunotherapy; Neurological disorders; Neuroscience; Therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • Amyotrophic Lateral Sclerosis / therapy*
  • Animals
  • Cell Line
  • DNA-Binding Proteins* / antagonists & inhibitors
  • DNA-Binding Proteins* / genetics
  • DNA-Binding Proteins* / metabolism
  • Dependovirus*
  • Disease Models, Animal
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / metabolism
  • Frontotemporal Dementia / pathology
  • Frontotemporal Dementia / therapy*
  • Mice
  • Mice, Transgenic
  • Mutation
  • Single-Chain Antibodies* / biosynthesis
  • Single-Chain Antibodies* / genetics
  • Transduction, Genetic*

Substances

  • DNA-Binding Proteins
  • Single-Chain Antibodies
  • TDP-43 protein, mouse

Grant support