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

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Figure 8

scAAV2/9-mediated delivery of scFv restores TDP-43 functions in the lumbar spinal cord of TDP-43A315T mice.

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scAAV2/9-mediated delivery of scFv restores TDP-43 functions in the lumb...
(A) Representative Western blot and quantification of nuclear POLDIP3 splicing in NTg (n = 7), A315T scAAV control–treated (n = 4), and A315T scAAV-VH7Vk9–treated (n = 4) individual mice (dots). One-way ANOVA P = 0.0008; ***P < 0.001 and *P < 0.05, by Tukey’s multiple comparisons test. (B) Representative Western blot and quantification of nuclear FUS in NTg (n = 6), A315T scAAV control–treated (n = 4), and A315T scAAV-VH7Vk9–treated (n = 3) individual mice (dots). One-way ANOVA P = 0.0112; *P < 0.05, by Tukey’s multiple comparisons test. Values are expressed as the fold change versus NTg. (C) Representative Western blot and quantification of cytoplasmic NFL in NTg (n = 3), A315T scAAV control–treated (n = 3), and A315T scAAV-VH7Vk9–treated (n = 3) individual mice (dots). One-way ANOVA P = 0.0042; **P < 0.01 and *P < 0.05, by Tukey’s multiple comparisons test. (D) Representative Western blot and quantification of cytoplasmic peripherin in NTg (n = 5), A315T scAAV control–treated (n = 6), and A315T scAAV-VH7Vk9–treated (n = 7) individual mice (dots). One-way ANOVA P = 0.0392; *P < 0.05, by Tukey’s multiple comparisons test. Protein levels were normalized to total transferred proteins (TTPs). Data represent the mean ± SEM. CTR, 8H11 scFv.