Mitsubishi Tanabe Pharma America Announces Publication of Preclinical Research on the Role of Edaravone in Mitigating TDP-43 Mislocalization in ALS

Results from this analysis were published in Free Radical Biology and Medicine

JERSEY CITY, N.J., March 25, 2025 /PRNewswire/ -- Mitsubishi Tanabe Pharma America, Inc. (MTPA) today announced the publication of new preclinical research in Free Radical Biology and Medicine, highlighting the role of edaravone in mitigating TDP-43 mislocalization, a hallmark feature observed in more than 97% of sporadic amyotrophic lateral sclerosis (ALS) cases. The study, conducted using induced pluripotent stem cell (iPSC)-derived motor neurons from a single patient with ALS, demonstrated that edaravone significantly reduced the abnormal cytoplasmic accumulation of TDP-43, restoring its nuclear localization. This mislocalization is a key driver of neuronal dysfunction and degeneration in ALS, and suggests that edaravone may offer a varied therapeutic approach for ALS by targeting oxidative stress and TDP-43 mislocalization through distinct molecular pathways.

"These findings help build upon our understanding of edaravone's potential effects in ALS," said Gustavo A. Suarez Zambrano, M.D., Vice President of Medical Affairs at MTPA. "By modulating TDP-43 pathology and engaging molecular pathways linked to neurodegeneration, edaravone may play a broader role in ALS management than previously understood and should continue to be studied."

"This study provides preclinical evidence that edaravone's MOA in ALS extends beyond its known antioxidant properties," said Satsuki Mikuriya, Research Scientist at MTPA and lead author of the study.

Key findings from the study include:

• In ALS patient-derived neurons from a patient with ALS harboring a TDP-43 mutation, edaravone significantly reduced the cytoplasmic accumulation of TDP-43, restoring its nuclear localization.
• Unlike vitamin C, edaravone preserved neurite structures and reduced neurotoxicity, supporting a unique mechanism of action.
• Edaravone treatment induced significant changes in gene expression as early as six hours post-treatment, with key pathways related to protein degradation and neuroprotection.
• Edaravone's effects were associated with modulation of the SIRT1-XBP1 pathway, a key regulator of cellular stress responses, suggesting a broader role in ALS neuroprotection.

This preclinical study was conducted using iPSC-derived motor neurons from a single ALS patient with a specific TDP-43 mutation (A382T) in an in vitro setting. Additional research in animal models and clinical settings (including those with other ALS-related mutations and patients with sporadic ALS) is needed to confirm these findings. Additionally, recent research has highlighted not only the toxic gain of function caused by TDP-43 aggregation but also the pathological sequences of TDP-43 loss of function due to its nuclear depletion. Further studies are required to explore how edaravone influences the loss of TDP-43 function.

While the study provides important new insights into edaravone's potential role in ALS treatment, further research is needed to confirm its effects in larger, more diverse ALS models and to explore its long-term impact on disease progression.

This analysis was funded and conducted by MTPA. Additional results can be found in the publication, titled, "Edaravone mitigates TDP-43 mislocalization in human amyotrophic lateral sclerosis neurons with potential implication of the SIRT1-XBP1 pathway."

About Mitsubishi Tanabe Pharma America, Inc.
Based in Jersey City, N.J., Mitsubishi Tanabe Pharma America, Inc. (MTPA) is a wholly-owned subsidiary of Mitsubishi Tanabe Pharma Corporation (MTPC). It was established by MTPC to develop and advance our pipeline as well as commercialize approved pharmaceutical products in North America. For more information, please visit www.mt-pharma-america.com or follow us on X (formerly Twitter), Facebook and LinkedIn.

About Mitsubishi Tanabe Pharma Corporation
Mitsubishi Tanabe Pharma Corporation (MTPC), the pharma arm of Mitsubishi Chemical Group (MCG), is one of the oldest pharmaceutical companies in the world, founded in 1678, and focusing on ethical pharmaceuticals. MTPC is headquartered in Doshomachi, Osaka, the birthplace of Japan's pharmaceutical industry. MTPC sets the MISSION of "Creating hope for all facing illness". To that end, MTPC is working on the disease areas of central nervous system, immuno-inflammation, diabetes and kidney, and cancer. MTPC is focusing on "precision medicine" to provide drugs with high treatment satisfaction by identifying patient populations with high potential for efficacy and safety. In addition, MTPC is working to develop "around the pill solutions" to address specific patient concerns based on therapeutic medicine, including prevention of diseases, pre-symptomatic disease care, prevention of aggravation and prognosis. For more information, go to https://www.mt-pharma.co.jp/e/

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SOURCE Mitsubishi Tanabe Pharma America