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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.

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


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.


Immunotherapy; Neurological disorders; Neuroscience; Therapeutics

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