Investigators concluded that the growing and testing of motor neurons from patient-derived induced pluripotent stem cells could be clinically used for the prediction of ropinirole’s efficacy as a treatment for patients with ALS.
Recently published research in the journal of Cell Stem Cell from an early clinical trial in Japan demonstrated safety with ropinirole, an investigational agent, with results showing delayed disease progression by 27.9 weeks on average in patients with amyotrophic lateral sclerosis (ALS).1 Although some patients showed more of a response to the treatment compared with others, investigators were able to predict clinical responsiveness in vitro using motor neurons derived from the patient’s stem cells.
In the trial, participants (n = 20) that were treated with ropinirole were physically more active compared to the patients who received placebo. Additionally, the physically active participants showed slower rates of decline in mobility, muscle strength, and lung function, and were less at risk of mortality; however, those on placebo who switched to ropinirole halfway through the trial did not experience these improvements, suggesting that the treatment may be useful only if started earlier and administered over a longer duration of time.
“ALS is totally incurable, and it’s a very difficult disease to treat,” senior author Hideyuki Okano, MD, PhD, professor of physiology at the Keio University School of Medicine in Tokyo said in a statement.1 “We previously identified ropinirole as a potential anti-ALS drug in vitro by iPSC drug discovery, and with this trial, we have shown that it is safe to use in patients with ALS and that it potentially has some therapeutic effect, but to confirm its effectiveness we need more studies, and we are now planning a phase 3 trial for the near future.”
Twenty patients with sporadic ALS who had an average of 20 months living with the disease were recruited from Keio University Hospital in Japan to investigate the safety and efficacy of ropinirole. It was noted that none of the patients enrolled into the study had carried any genes that were predisposing to the disease.1 In the first 24 weeks, the trial was double-blinded and after that period, all the patients who wanted to continue were knowingly administered ropinirole. For a full year, 7 of 13 patients who were given ropinirole and 1 among 7 patients who were given placebo followed by ropinirole were monitored despite some patients dropping out because of the COVID-19 pandemic.
Several different measures were used throughout the trial and 4 weeks following the retreatment period to determine the efficacy of the treatment to slow the progression of ALS. Some of these measures included the patients’ self-reported physical activity and their independent ability to eat and drink, wearable device data activity, and provider-measured changes in mobility, muscle strength, and lung function.
“We found that ropinirole is safe and tolerable for patients with ALS and shows therapeutic promise at helping them sustain daily activity and muscle strength,” lead author Satoru Morimoto, MD, a neurologist at the Keio University School of Medicine in Tokyo said in a statement.1
The researchers also explored the mechanisms of ropinirole’s effects and investigated the potential molecular markers of the disease by generating induced pluripotent stem cells from patients’ blood, growing them into motor neurons. In comparison with healthy motor neurons, the motor neurons from patients with ALS displayed distinctive differences in their structure, gene expression, and metabolite concentrations, although ropinirole reduced these differences.
More specifically, the motor neurons grown from patients with ALS experienced shorter neurites compared with the healthy motor neurons, although these axons grew a more normal length when treated with ropinirole. Also, 29 genes relating to cholesterol synthesis were recognized. These genes tended to increase in motor neurons as observed in the patients with ALS, yet ropinirole subdued the gene expressions over time. Notably, investigators reported that lipid peroxide is a good surrogate marker for estimating ropinirole’s effect on both in vitro and clinically.
“We found a very striking correlation between a patient’s clinical response and the response of their motor neurons in vitro,” Morimoto said in a statement.1 “Patients whose motor neurons responded robustly to ropinirole in vitro had a much slower clinical disease progression with ropinirole treatment, while suboptimal responders showed much more rapid disease progression despite taking ropinirole.”