Sustained therapeutic benefits by transient reduction of TDP-43 using ENA-modified antisense oligonucleotides in ALS/FTD mice

• Published in: Molecular therapy. Nucleic acids Vol. 31; pp. 353 - 366
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.03.2023; American Society of Gene & Cell Therapy; Elsevier
• Subjects: aggregation; amyotrophic lateral sclerosis; antisense oligonucleotides; ENA; frontotemporal dementia; MT: Oligonucleotides: Therapies and Applications; Original; TDP-43; therapy; MT: Oligonucleotides: Therapies and Applications; TDP-43; therapy; antisense oligonucleotides; frontotemporal dementia; ENA; aggregation; amyotrophic lateral sclerosis
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2023.01.006

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. [Display omitted] 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.