ALS治療薬候補としてのロピニロール塩酸塩

Ropinirole Hydrochloride, a Candidate Drug for ALS Treatment

疾患特異的iPS細胞（iPSC）を用いて家族性および孤発性ALS患者から脊髄運動ニューロンを作製し，in vitroで疾患表現型を再現した。1,232種類の既存薬ライブラリーから有効性スクリーニングを行い，ドラッグ・リポジショニングとしてロピニロール塩酸塩を用いた医師主導治験を開始した。ALS患者に対する安全性・忍容性および有効性を探索するプラセボ対照，二重盲検期および非盲検継続投与期から成る本第Ⅰ/Ⅱa相試験は，本邦におけるALSに対するiPSC創薬の試金石となる。

Abstract

We performed drug screening using motor neurons derived from disease-specific induced pluripotent stem cells (iPSCs) for amyotrophic lateral sclerosis (ALS) and found that ropinirole hydrochloride prevented motor neuron death. We have started a randomized clinical trial testing ropinirole hydrochloride in ALS patients in December 2018. This is a phase I/IIa randomized, double-blind, placebo-controlled, single-center, open-label continuation clinical trial. The primary aim is to assess the safety and tolerability of ropinirole hydrochloride in patients with ALS. Secondary aims include the following effectiveness evaluations: ALSFRS-R, quantitative muscle strength by a hand-held dynamometer, muscle volume by CT scan, forced vital capacity, physical activity by an activity tracker, survival, ALSAQ40 scale, and a Zarit Caregiver Burden Interview. Moreover, we will perform an efficacy evaluation using subjects-derived iPSCs/motor neurons and assess plasma/CSF biomarkers (TDP-43, and ALS-related RNA/micro RNA) as exploratory research questions. Ropinirole hydrochloride potentially targets multiple mechanisms of ALS pathology (i.e., oxidative stress, mitochondrial dysfunction, and abnormal aggregation of TDP-43/FUS protein, which is representative of the ALS phenotype), with promising preclinical study results based on iPSC research. The availability of the drug suggests that rapid translation to daily clinical use might be possible. Our trial will provide reliable and important data for further potential trials. The results will appear in March 2021.