• Interview "I investigate ALS from the CNIO because we have to give visibility to this disease"

A treatment commonly used for Parkinson's may also be useful for ALS. The dopamine agonist ropinirole, indicated in the treatment of Parkinson's and restless legs syndrome, has obtained encouraging preliminary results in amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease in a small phase I/II clinical trial. Japanese researchers published the details of their research in the journal Cell Stem Cell on Thursday.

Previously, the team of physiologist Hideyuki Okano, from the Faculty of Medicine of Keio University (Tokyo) and coordinator of the work, had identified the potential of ropinirole as a treatment for ALS in an in vitro study in motor neurons derived from induced pluripotent stem cells (iPSCs) of ALS patients.

After this first step, the researchers recruited 20 patients with sporadic ALS who were treated at Keio University Hospital and who on average had been living with the disease for 20 months.

In the first 24 weeks the trial was double-blind and from this point, ropinirole was offered to all participants. During follow-up there were many dropouts, some due to the Covid-19 pandemic but none due to safety concerns, so that only 7 of the 13 patients in the ropinirole group and 1 of the 7 in the placebo group completed the study.

To determine whether the drug is effective in slowing progression, the researchers evaluated changes in patients' self-reported physical activity and ability to eat and drink independently, data from electronic devices to measure physical activity, and changes assessed by medical personnel in mobility, muscle strength and lung function.


"With this trial we have shown that the use [of ropinirole] is safe in ALS patients and that it potentially has some therapeutic effect, but to confirm its efficacy we need more studies," Okano said in a press release released by the journal. In this sense, he affirms that it is among his next plans to carry out a phase III trial.

At 24 weeks, no differences were observed between the two groups in the ALSFRS-R functional assessment scale of ALS patients. However, after 48 weeks, when the open-label phase of the trial ended and only one patient remained in the placebo group, the ropinirole group was seen to have a delay in disease progression measured by this 27.9-month scale.

Patients who received ropinirole during the first and second phase of the trial were more physically active than those in the placebo group. They also showed slower rates of decreased mobility, muscle strength and lung function, and more likely to survive. But patients included in the placebo group who started taking ropinirole from week 24 did not experience these improvements, suggesting that this drug would only be useful if started earlier and maintained for longer.

Mechanism and molecular markers

The team also investigated the possible mechanism that would explain the drug's effect on disease, as well as possible molecular markers. Compared to motor neurons in healthy people, the researchers describe differences in the structure, gene expression and concentration of metabolites in the cells of ALS patients and note that the drug would reduce the differences. They also indicate that ropinirole would potentially inhibit the SREBP2 pathway of cholesterol synthesis.

"We found a very striking correlation between a patient's clinical response and their motor neuron response in vitro," said neurologist Satoru Morimoto of Keio University School of Medicine and first author of the paper in Cell Stem Cell. The researchers advocate this way of testing the drug on motor neurons created in the lab to predict the efficacy of the treatment.

Specifically, motor neurons from the patients had shorter axons than healthy motor neurons, but exposure to ropinirole caused them to grow to a more normal length. They also identified 29 genes related to cholesterol synthesis that tended to increase in motor neurons in ALS, but the treatment suppressed their gene expressions. They also state that lipid peroxide in cerebrospinal fluid would be a good marker of ropinirole response, both in vitro and clinically.


Francisco Javier Rodríguez de Rivera, coordinator of the Study Group of Neuromuscular Diseases of the Spanish Society of Neurology (SEN) and specialist of the ALS Unit of the Hospital La Paz - Carlos III (Madrid), is very cautious about the conclusions reached by the authors.

The expert explains to this medium that this way of discovering drugs from induced pluripotent stem cells of patients is increasingly extended in research in ALS and other neurodegenerative diseases, such as Friedrich's ataxia, and is not always a guarantee of success. In his opinion, the study does not dispel doubts about the potential of ropinirole either: "This phase I/II trial does not allow us to reach any clear conclusions because the data are very poor," he warns.

He especially criticizes that the researchers point out that the drug slowed the progression by six months, but that this effect was not seen in the double-blind phase but only at the end of the 48 weeks of follow-up, when only one patient remained in the placebo group.

On the other hand, he warns that "the main mistake is in its starting point, and is to consider that ALS is a unique disease," he says. "It is increasingly clear that it is a syndrome, which has many forms of onset, although in the end it always leads to motor neuron failure. Probably in a few years we will see that including patients without a genetic characterization in the same study does not make any sense."

From the United Kingdom, researchers Michael Swash, professor of neurology at Barts and London School of Medicine, and Brian Dickie, director of research at the Motor Neurone Disease Association, in statements to SMC Spain, point out the necessary reservations to this study in the initial phase.

Swash recalls that the ALS research community has been working for a long time on drug repositioning and that ropinirole may be one of the drugs marketed for other indications that demonstrate usefulness in the disease. But for this, he affirms that it is first necessary to know better its mechanism of action. who could benefit and their safety profile in ALS.

However, the expert indicates that "there are interesting parallels in the accumulation of proteins in the neuronal cytosol between Parkinson's disease and ALS that should be explored."

Dickie said: "Although these results may be of some interest to the research community, the clinical trial is too small and the results too preliminary to draw valid conclusions.

According to the criteria of The Trust Project

Learn more