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J Clin Invest. 2019 Feb 25;130. pii: 123931. doi: 10.1172/JCI123931. eCollection 2019 Feb 25.

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

Author information

1
CERVO Brain Research Centre, Québec, Québec, Canada.
2
MITOVASC Institute, Centre National de la Recherche Scientifique (CNRS) 6015, INSERM U1083, University of Angers, Angers, France.
3
Department of Psychiatry and Neuroscience, Université Laval, Québec City, Québec, Canada.

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

PMID:
30667370
DOI:
10.1172/JCI123931
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