Sustained therapeutic benefits by transient reduction of TDP-43 using ENA-modified antisense oligonucleotides in ALS/FTD mice.
Sustained therapeutic benefits by transient reduction of TDP-43 using ENA-modified antisense oligonucleotides in ALS/FTD mice.
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DOI：
10.1016/j.omtn.2023.01.006
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发表时间：
2023-03-14
期刊：
影响因子：
--
通讯作者：
Nagai, Yoshitaka
中科院分区：
文献类型：
--
作者：
Takeuchi, Toshihide;Maeta, Kazuhiro;Ding, Xin;Oe, Yukako;Takeda, Akiko;Inoue, Mana;Nagano, Seiichi;Fujihara, Tsuyoshi;Matsuda, Seiji;Ishigaki, Shinsuke;Sahashi, Kentaro;Minakawa, Eiko N.;Mochizuki, Hideki;Neya, Masahiro;Sobue, Gen;Nagai, Yoshitaka
TDP-43 异常聚集到受影响神经元的细胞质内含物中是肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 的病理标志。尽管 TDP-43 如何形成细胞质聚集体并导致 ALS/FTD 患者的神经变性尚不清楚，但降低细胞 TDP-43 水平可能会阻止聚集并拯救神经元免受 TDP-43 毒性。为了解决这个问题，我们使用2'-O,4'-C-乙烯核酸（ENA）（一种具有高稳定性的修饰核酸）开发了针对人TDP-43的gapmer型反义寡核苷酸（ASO），并测试了使用ENA修饰的ASO降低TDP-43水平的治疗潜力。我们证明，将 ENA 修饰的 ASO 脑室内注射到表达人 TDP-43 的 ALS/FTD 小鼠模型中，可有效降低大脑和脊髓中的 TDP-43 水平。令人惊讶的是，即使在 TDP-43 水平恢复到初始水平后，对 TDP-43 小鼠单次注射 ENA 修饰的 ASO 也能导致行为异常的持久改善和细胞质 TDP-43 聚集的抑制。我们的结果表明，使用 ENA 修饰的 ASO 短暂降低 TDP-43 可在体内带来持续的治疗益处，表明通过降低 TDP-43 水平来治疗 TDP-43 蛋白病（包括 ALS/FTD）的疾病缓解疗法的可能性。 TDP-43 在肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 的发病机制中发挥着核心作用。竹内等人。证明使用间隙聚体型反义寡核苷酸瞬时减少 TDP-43 可抑制细胞质 TDP-43 聚集和体内疾病表型，表明 TDP-43 降低方法对于 ALS/FTD 治疗的治疗潜力。
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. TDP-43 plays central roles in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Takeuchi et al. demonstrate that the transient reduction of TDP-43 using gapmer-type antisense oligonucleotides suppresses cytoplasmic TDP-43 aggregation and disease phenotypes in vivo, indicating the therapeutic potential of the TDP-43-lowering approach for ALS/FTD treatment.
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内源性TDP-43而不是FUS，通过G3BP导致应力颗粒组件。
影响因子：
15.1
作者：
Aulas A;Stabile S;Vande Velde C
通讯作者：
Vande Velde C
影响因子：
14.9
作者：
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Onodera O
影响因子：
30.8
作者：
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通讯作者：
Wszolek ZK
影响因子：
16.2
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Cleveland DW
影响因子：
14.8
作者：
Barmada, Sami J.;Serio, Andrea;Arjun, Arpana;Bilican, Bilada;Daub, Aaron;Ando, D. Michael;Tsvetkov, Andrey;Pleiss, Michael;Li, Xingli;Peisach, Daniel;Shaw, Christopher;Chandran, Siddharthan;Finkbeiner, Steven
通讯作者：
Finkbeiner, Steven