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.
View: Text | PDF
Research Article Neuroscience

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

×

Figure 7

scAAV2/9-mediated delivery of scFv ameliorates motor performance and pathological defects in TDP-43A315T mice.

Options: View larger image (or click on image) Download as PowerPoint
scAAV2/9-mediated delivery of scFv ameliorates motor performance and pat...
(A) Grip strength analysis showing the percentage of maximum performance of each single mouse and the number of individual mice (dots) analyzed. Two-way ANOVA corrected for repeated-measures interaction P = 0.823, time P = 0.0512, scFv P < 0.0001; *P < 0.05 versus control scFv, by uncorrected Fisher’s LSD. (B) Percentage of total NMJs. n = 3 individual mice (dots). Two-way ANOVA P = 0.0063; *P < 0.05 versus control scFv, by uncorrected Fisher’s LSD test. (C) Representative image and quantification of hTDP-43 (green) in motor neurons (CHAT, red) of lumbar spinal cord. The cytoplasmic to nuclear ratio of the TDP-43 integrated density of each cell was plotted according to the area of the cell. Data represent single-cell ratios (dots) analyzed from 4 individual mice. Solid line indicates the linear regression and dotted lines the 95% CIs. Slope diversity P = 0.0033. Scale bars: 10 μm. Representative blots and quantification of nuclear and cytoplasmic (D) and insoluble (E) pan–TDP-43 in lumbar spinal cord from 3 individual mice (dots). TDP-43 was normalized to p84 or GAPDH fraction markers (D) or to Ponceau (E), and values are expressed as the fold change versus control scFv. (B–E) Statistical significance was determined by unpaired t test. Data represent the mean ± SEM. CTR, 8H11 scFv.