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 April 1, 2019; First 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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Figure 6

Intracortical injection of scAAV2/9 encoding for scFv antibody improves cognitive deficits and restores TDP-43 mislocalization in TDP-43G348C mice.

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Intracortical injection of scAAV2/9 encoding for scFv antibody improves ...
NOR test 2 months (A) and 4 months (B) after injection. Graphs in A and B show the percentage of time spent with objects and the number of individual mice tested (dots). (A) Two-way ANOVA P = 0.0004; ***P < 0.001 and *P < 0.05, by Sidak’s multiple comparisons test. (B) Two-way ANOVA P < 0.0001; ***P < 0.001 for familiar versus novel object, by Sidak’s multiple comparisons test; *P < 0.05 and **P < 0.01 among groups, by uncorrected Fisher’s least significant difference (LSD) test. (C) Quantification of hTDP-43 mislocalization in cortical neurons and representative images. Data represent the cytoplasmic to nuclear ratio of TDP-43 integrated density. n = 3 individual mice (dots). Two-way ANOVA interaction P = 0.979, hemisphere P = 0.3747, scFv P < 0.0001; **P < 0.01 versus control scFv, by Sidak’s multiple comparisons test. Shown are hTDP-43 (green) and merged images of hTDP-43, NeuN (red), and Hoechst (nuclei, blue). Scale bars: 20 μm. Representative blots and quantification of nuclear and cytoplasmic (D) and insoluble (E) hTDP-43 in ipsilateral cortices. n = 3 individual mice (dots). hTDP-43 was normalized to p84 or GAPDH fraction markers (D) and to Ponceau (E). Values are expressed as the fold change versus control scFv. Statistical analysis was done by unpaired t test. Data represent the mean ± SEM. CTR, 8H11 scFv.