July 22, 2024
Keio University
Japanese Foundation for Cancer Research
A joint research group led by Professor Hideyuki Okano, Director/Professor of the Keio University Regenerative Medicine Research Center (KRM) (at the time of research: Professor, Department of Physiology, Keio University School of Medicine); Kurizumi Kato, a fifth-year student at the Keio University School of Medicine; Project Associate Professor Satoru Morimoto of the Keio Frontier Research & Education Collaborative Square (K-FRECS) [K-FRECS at Tonomachi] (at the time of research: Senior Lecturer, Department of Physiology, Keio University School of Medicine); and Project Leader Koji Ueda of the Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, conducted a longitudinal and comprehensive quantification of the protein composition of extracellular vesicles (EVs) in the blood and cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) patients who participated in the Phase I/IIa investigator-initiated trial of ropinirole hydrochloride (ROPI) (the ROPALS trial). The group discovered that the protein composition of body fluid-derived EVs in patients with sporadic ALS (SALS) differs from that of healthy individuals, that this change also occurs with the longitudinal progression of SALS pathology, and that ROPI administration suppresses this change. Additionally, research using induced pluripotent stem cell (iPSC)-derived astrocytes (iPasts) suggested that ROPI may activate the D2R-CRYAB pathway, which suppresses neuroinflammation. Furthermore, through biomarker discovery using machine learning models, they identified distinct protein groups presumed to be useful for prognosis prediction and diagnosis.
EVs are secreted by most cell types into body fluids like blood and CSF. As they contain substances such as proteins and nucleic acids, they are thought to be involved in the intercellular transfer of biomaterials. Their contribution to disease and utility as biomarkers have been suggested in conditions such as malignant tumors and neurodegenerative diseases like SALS. However, the longitudinal and comprehensive EV protein composition in SALS and useful biomarkers for prognosis prediction were not well understood. Furthermore, the changes in EV protein composition induced by ROPI, which was suggested in the ROPALS trial to suppress disease progression, remained unknown. In this study, the joint research group conducted this research as a reverse translational research (rTR) study of the ROPALS trial, examining the comprehensive EV protein composition using longitudinal patient-derived body fluids to clarify these aspects.
These findings partially elucidate the pathology of SALS and the therapeutic mechanism of ROPI, and are considered to provide important insights for understanding SALS and developing treatment strategies. The results of this study were published in Inflammation and Regeneration , the official international journal of the Japanese Society of Inflammation and Regeneration (JSIR), on July 12, 2024, at 7:00 PM (JST).
For the full press release, please see below.