Virus-mediated delivery of antibody targeting TAR DNA-binding protein-43 mitigates associated neuropathology
Silvia Pozzi, … , Claude Gravel, Jean-Pierre Julien
Silvia Pozzi, … , Claude Gravel, Jean-Pierre Julien
Published January 22, 2019
Citation Information: J Clin Invest. 2019;129(4):1581-1595. https://doi.org/10.1172/JCI123931.
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Research Article Neuroscience Therapeutics

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

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.

Authors

Silvia Pozzi, Sai Sampath Thammisetty, Philippe Codron, Reza Rahimian, Karine Valérie Plourde, Geneviève Soucy, Christine Bareil, Daniel Phaneuf, Jasna Kriz, Claude Gravel, Jean-Pierre Julien

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