Sustained therapeutic benefits by transient reduction of TDP-43 using ENA-modified antisense oligonucleotides in ALS/FTD mice
The abnormal aggregation of TDP-43 into cytoplasmic inclusions in affected neurons is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although how TDP-43 forms cytoplasmic aggregates and causes neurodegeneration in patients with ALS/FTD remains uncle...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-03-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253123000094 |
| _version_ | 1797936412186640384 |
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| author | Toshihide Takeuchi Kazuhiro Maeta Xin Ding Yukako Oe Akiko Takeda Mana Inoue Seiichi Nagano Tsuyoshi Fujihara Seiji Matsuda Shinsuke Ishigaki Kentaro Sahashi Eiko N. Minakawa Hideki Mochizuki Masahiro Neya Gen Sobue Yoshitaka Nagai |
| author_facet | Toshihide Takeuchi Kazuhiro Maeta Xin Ding Yukako Oe Akiko Takeda Mana Inoue Seiichi Nagano Tsuyoshi Fujihara Seiji Matsuda Shinsuke Ishigaki Kentaro Sahashi Eiko N. Minakawa Hideki Mochizuki Masahiro Neya Gen Sobue Yoshitaka Nagai |
| author_sort | Toshihide Takeuchi |
| collection | DOAJ |
| description | The abnormal aggregation of TDP-43 into cytoplasmic inclusions in affected neurons is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although how TDP-43 forms cytoplasmic aggregates and causes neurodegeneration in patients with ALS/FTD remains unclear, reducing cellular TDP-43 levels is likely to prevent aggregation and to rescue neurons from TDP-43 toxicity. To address this issue, here we developed gapmer-type antisense oligonucleotides (ASOs) against human TDP-43 using 2′-O,4′-C-ethylene nucleic acids (ENAs), which are modified nucleic acids with high stability, and tested the therapeutic potential of lowering TDP-43 levels using ENA-modified ASOs. We demonstrated that intracerebroventricular administration of ENA-modified ASOs into a mouse model of ALS/FTD expressing human TDP-43 results in the efficient reduction of TDP-43 levels in the brain and spinal cord. Surprisingly, a single injection of ENA-modified ASOs into TDP-43 mice led to long-lasting improvement of behavioral abnormalities and the suppression of cytoplasmic TDP-43 aggregation, even after TDP-43 levels had returned to the initial levels. Our results demonstrate that transient reduction of TDP-43 using ENA-modified ASOs leads to sustained therapeutic benefits in vivo, indicating the possibility of a disease-modifying therapy by lowering TDP-43 levels for the treatment of the TDP-43 proteinopathies, including ALS/FTD. |
| first_indexed | 2024-04-10T18:30:24Z |
| format | Article |
| id | doaj.art-e9b6e963c4c34b85be2d7b931b43c025 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-04-10T18:30:24Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-e9b6e963c4c34b85be2d7b931b43c0252023-02-02T04:48:17ZengElsevierMolecular Therapy: Nucleic Acids2162-25312023-03-0131353366Sustained therapeutic benefits by transient reduction of TDP-43 using ENA-modified antisense oligonucleotides in ALS/FTD miceToshihide Takeuchi0Kazuhiro Maeta1Xin Ding2Yukako Oe3Akiko Takeda4Mana Inoue5Seiichi Nagano6Tsuyoshi Fujihara7Seiji Matsuda8Shinsuke Ishigaki9Kentaro Sahashi10Eiko N. Minakawa11Hideki Mochizuki12Masahiro Neya13Gen Sobue14Yoshitaka Nagai15Life Science Research Institute, Kindai University, 377-2 Ohnohigashi, Osaka-Sayama, Osaka 589-8511, Japan; Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; Corresponding author: Toshihide Takeuchi, PhD, Life Science Research Institute, Kindai University, 377-2 Ohnohigashi, Osaka-Sayama, Osaka 589-8511, JapanDepartment of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, JapanDepartment of Neurology, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osaka-Sayama, Osaka 589-8511, Japan; Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, JapanDepartment of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, JapanDepartment of Neurology, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osaka-Sayama, Osaka 589-8511, Japan; Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, JapanDepartment of Neurology, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osaka-Sayama, Osaka 589-8511, JapanDepartment of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, JapanKNC Laboratories Co., Ltd., Kobe, Hyogo 650-0047, JapanKNC Laboratories Co., Ltd., Kobe, Hyogo 650-0047, JapanDepartment of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, JapanDepartment of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, JapanDepartment of Neurophysiology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, JapanDepartment of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, JapanKNC Laboratories Co., Ltd., Kobe, Hyogo 650-0047, JapanDepartment of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, JapanLife Science Research Institute, Kindai University, 377-2 Ohnohigashi, Osaka-Sayama, Osaka 589-8511, Japan; Department of Neurology, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osaka-Sayama, Osaka 589-8511, Japan; Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; Corresponding author: Yoshitaka Nagai, MD, PhD, Department of Neurology, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osaka-Sayama, Osaka 589-8511, JapanThe abnormal aggregation of TDP-43 into cytoplasmic inclusions in affected neurons is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although how TDP-43 forms cytoplasmic aggregates and causes neurodegeneration in patients with ALS/FTD remains unclear, reducing cellular TDP-43 levels is likely to prevent aggregation and to rescue neurons from TDP-43 toxicity. To address this issue, here we developed gapmer-type antisense oligonucleotides (ASOs) against human TDP-43 using 2′-O,4′-C-ethylene nucleic acids (ENAs), which are modified nucleic acids with high stability, and tested the therapeutic potential of lowering TDP-43 levels using ENA-modified ASOs. We demonstrated that intracerebroventricular administration of ENA-modified ASOs into a mouse model of ALS/FTD expressing human TDP-43 results in the efficient reduction of TDP-43 levels in the brain and spinal cord. Surprisingly, a single injection of ENA-modified ASOs into TDP-43 mice led to long-lasting improvement of behavioral abnormalities and the suppression of cytoplasmic TDP-43 aggregation, even after TDP-43 levels had returned to the initial levels. Our results demonstrate that transient reduction of TDP-43 using ENA-modified ASOs leads to sustained therapeutic benefits in vivo, indicating the possibility of a disease-modifying therapy by lowering TDP-43 levels for the treatment of the TDP-43 proteinopathies, including ALS/FTD.http://www.sciencedirect.com/science/article/pii/S2162253123000094MT: Oligonucleotides: Therapies and ApplicationsTDP-43antisense oligonucleotidesamyotrophic lateral sclerosisfrontotemporal dementiatherapy |
| spellingShingle | Toshihide Takeuchi Kazuhiro Maeta Xin Ding Yukako Oe Akiko Takeda Mana Inoue Seiichi Nagano Tsuyoshi Fujihara Seiji Matsuda Shinsuke Ishigaki Kentaro Sahashi Eiko N. Minakawa Hideki Mochizuki Masahiro Neya Gen Sobue Yoshitaka Nagai Sustained therapeutic benefits by transient reduction of TDP-43 using ENA-modified antisense oligonucleotides in ALS/FTD mice Molecular Therapy: Nucleic Acids MT: Oligonucleotides: Therapies and Applications TDP-43 antisense oligonucleotides amyotrophic lateral sclerosis frontotemporal dementia therapy |
| title | Sustained therapeutic benefits by transient reduction of TDP-43 using ENA-modified antisense oligonucleotides in ALS/FTD mice |
| title_full | Sustained therapeutic benefits by transient reduction of TDP-43 using ENA-modified antisense oligonucleotides in ALS/FTD mice |
| title_fullStr | Sustained therapeutic benefits by transient reduction of TDP-43 using ENA-modified antisense oligonucleotides in ALS/FTD mice |
| title_full_unstemmed | Sustained therapeutic benefits by transient reduction of TDP-43 using ENA-modified antisense oligonucleotides in ALS/FTD mice |
| title_short | Sustained therapeutic benefits by transient reduction of TDP-43 using ENA-modified antisense oligonucleotides in ALS/FTD mice |
| title_sort | sustained therapeutic benefits by transient reduction of tdp 43 using ena modified antisense oligonucleotides in als ftd mice |
| topic | MT: Oligonucleotides: Therapies and Applications TDP-43 antisense oligonucleotides amyotrophic lateral sclerosis frontotemporal dementia therapy |
| url | http://www.sciencedirect.com/science/article/pii/S2162253123000094 |
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