Our laboratory previously established spinal motor neurons (MN) from induced-pluripotent stem cells (iPSCs) prepared from both sporadic and familial ALS patients, and successfully recapitulated disease-specific pathophysiological processes. We next searched for effective drugs capable of slowing the progression of ALS using a drug library of 1232 existing compounds and discovered that ropinirole hydrochloride prevented MN death. In December 2018, we started an investigator-initiated clinical trial testing ropinirole hydrochloride extended-release tablets in ALS patients. This is an on-going phase I/IIa randomized, double-blind, placebo-controlled, single-center, open-label continuation clinical trial (UMIN000034954). The primary aim is to assess the safety and tolerability of ropinirole hydrochloride in patients with ALS. We will also perform an efficacy evaluation using patient-derived iPSCs/MN. Major inclusion criteria were as follows: 1) 'clinically possible and laboratory-supported ALS', 'clinically probable ALS' or 'clinically definite ALS', according to the criteria for the diagnosis of ALS (El Escorial revised) and within 60 months after disease onset; 2) change in ALSFRS-R score of -2 to -5 points during the 12-week run-in period. Finally, 15 patients will be assigned to the active drug and 5 patients to the placebo. Our trial will be a touchstone trial for iPSC-based drug development strategies.

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.