Parkinson’s drug ropinirole shown to be safe and well-tolerated in ALS patients in early clinical trial

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a fatal motor neuron disease that causes people to gradually lose muscle control. There is no cure, and current treatments focus on relieving symptoms and providing supportive care. Report the diary of June 1 cell stem cellJapanese researchers have shown in an early clinical trial that the Parkinson’s drug ropinirole can be safely used in people with ALS, slowing disease progression by an average of 27.9 weeks.

Some patients were more responsive to ropinirole treatment than others, allowing researchers to predict clinical response in vitro Use patient stem cell-derived motor neurons.

ALS is a completely incurable disease and very difficult to treat.We previously identified ropinirole as a potential anti-ALS drug in vitro An iPSC drug discovery study, the current study showed that it is safe to use and may have some therapeutic benefit in ALS patients, but further research is needed to confirm efficacy. Yes, and a Phase 3 trial is currently being planned. for the near future. “

Hideyuki Okano, lead author, physiologist, Keio University School of Medicine

To test the safety and efficacy of ropinirole in patients with sporadic (i.e., non-familial) ALS, the research team recruited 20 patients undergoing treatment at Keio University Hospital in Japan. None of the patients had a predisposing gene for the disease, and on average he lived with ALS for 20 months.

The trial was double-blind for the first 24 weeks. That is, patients and physicians did not know which patients received ropinirole and which received placebo. Ropinirole was then intentionally administered to all patients who wished to continue for the next 24 weeks. Because many patients dropped out prematurely, partly due to the COVID-19 pandemic, 13 of 7 ropinirole-treated patients were monitored throughout the year, ropinirole followed by placebo Only 1 in 7 treated patients. However, no patient dropped out for safety reasons.

To determine whether the drug was effective in slowing the progression of ALS, the team monitored various measurements during the trial and for four weeks after treatment ended. These include changes in patient self-reported physical activity and ability to eat and drink independently, activity data from wearable devices, and physician-measured changes in mobility, muscle strength, and lung function.

“We found that ropinirole is safe and tolerable in patients with ALS and shows therapeutic promise in helping maintain daily activities and muscle strength,” said lead author Keio, Tokyo, Japan. Satoru Morimoto, a neurologist at Keio University School of Medicine, said.

Patients who received ropinirole in both phases of the trial were more physically active than those in the placebo group. They also had slower declines in mobility, muscle strength, and lung function, and were more likely to survive.

As the trials progressed, the benefits of ropinirole compared to placebo became increasingly pronounced. However, patients in the placebo group who started taking ropinirole midway through the trial did not show this improvement, suggesting that ropinirole treatment is only useful if treatment is started early and given over a longer period of time. suggests that there is a possibility.

The researchers then investigated the mechanisms behind ropinirole’s effects and looked for molecular markers of the disease.To do this, they induced pluripotent stem cells Harvested from the patient’s blood, these cells were grown into motor neurons in the lab. They found that compared to healthy motor neurons, motor neurons from ALS patients displayed distinct differences in structure, gene expression, and metabolite concentrations, but ropinirole treatment reduced these differences.

Specifically, motor neurons grown from ALS patients had shorter neurites compared to healthy motor neurons, but when the cells were treated with ropinirole, these axons returned to a more normal length. I grew up. The research team also identified 29 genes associated with cholesterol synthesis that tended to be upregulated in motor neurons of ALS patients, whose gene expression was suppressed over time by ropinirole treatment. They also identified lipid peroxides as a good surrogate marker for estimating ropinirole effects. in vitro and clinically.

“We found a very significant correlation between the patient’s clinical response and the motor neuron response. in vitro“Patients whose motor neurons responded strongly to ropinirole,” Morimoto said. in vitro Ropinirole-treated patients had much slower clinical disease progression, whereas suboptimal responders had much more rapid disease progression despite taking ropinirole. “

The researchers suggest that this method of growing and testing motor neurons from patient-derived induced pluripotent stem cells could be used clinically to predict the effect of a drug on a particular patient. It states that It is unclear why some patients are more responsive to ropinirole than others, but the researchers believe it is likely due to genetic differences, which they hope to determine in future studies. I believe.