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

TitleVirus-mediated delivery of antibody targeting TAR DNA-binding protein-43 mitigates associated neuropathology.
Publication TypeJournal Article
Year of Publication2019
AuthorsPozzi, S, Thammisetty, SSampath, Codron, P, Rahimian, R, Plourde, KValérie, Soucy, G, Bareil, C, Phaneuf, D, Kriz, J, Gravel, C, Julien, J-P
JournalJ Clin Invest
Volume129
Issue4
Pagination1581-1595
Date Published2019 02 25
ISSN1558-8238
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.

DOI10.1172/JCI123931
Alternate JournalJ. Clin. Invest.
PubMed ID30667370
PubMed Central IDPMC6436898