Amyotrophic lateral sclerosis (ALS) is an incurable disease that impairs the motor neurons that control muscle movement. Those affected progressively lose control of their muscles and suffer paralysis in the extremities and loss of the ability to speak, swallow and breathe, which is why most die from respiratory failure.
Currently available therapies help alleviate the symptoms of ALS, but do not stop the progression of the disease, and therefore any novelty in treatment represents a path of hope for patients. Now, scientists at the Keio University School of Medicine in Tokyo have tested a drug used to treat Parkinson’s – ropinirole – in 20 people with amyotrophic lateral sclerosis and found that it slows the progression of ALS by an average of 27, 9 weeks.
“We previously identified ropinirole as a potential ALS drug in vitro through induced pluripotent stem cell (iPSC) drug discovery, and with this trial we have shown that it is safe to use in ALS patients and that it possibly has some therapeutic effect, but to confirm its efficacy we need more studies, and now we are planning a phase 3 trial for the near future,” said physiologist Hideyuki Okano of the Keio University School of Medicine in Tokyo and author principal of this phase I/II clinical trial whose results have been published in Cell Stem Cell.
Ropinirole is safe and shows therapeutic effects in people with ALS
The study involved 20 patients who were cared for at the Keio University Hospital in Japan, none of whom carried genes that predispose to developing the disease and, on average, had been suffering from ALS for 20 months. During the first 24 weeks neither patients nor physicians knew who was taking ropinirole and who was receiving placebo (double-blind trial), while in the following 24 weeks all patients who decided to continue knew that they were taking the drug.
“We found that ropinirole is safe and tolerable for ALS patients and shows therapeutic promise in helping them maintain daily activity and muscle strength.”
Only seven of the 13 patients treated with ropinirole and one of the seven who received placebo followed by ropinirole were followed up completely throughout the year because many withdrew from the study due to the COVID-19 pandemic. The researchers monitored various measures during the study and for four weeks after treatment ended, including changes in patients’ self-reported physical activity, their ability to eat and drink independently, as well as recorded activity data. in wearable devices and others that doctors measured in your mobility, muscle strength, and lung function.
The results showed that those patients who received ropinirole during the two phases of the trial were more physically active than those in the placebo group, had slower rates of decline in mobility, muscle strength, and lung function, and were more likely to of survive.
“We found that ropinirole is safe and tolerable for ALS patients and shows therapeutic promise in helping them maintain daily activity and muscle strength,” said first author Satoru Morimoto, a neurologist at Keio University School of Medicine. in Tokyo.
The benefits of ropinirole became increasingly apparent as the study progressed compared to placebo, but patients in the placebo group who started ropinirole midway through the trial did not experience these improvements, suggesting that ropinirole treatment may be useful only if started early and administered over a longer period of time.
Ropinirole mechanism of action
The authors of the paper then studied the mechanisms related to the effects of ropinirole and searched for molecular markers of the disease. To do this, they generated induced pluripotent stem cells from the patients’ blood and grew them into motor neurons in the laboratory. They found that motor neurons from ALS patients showed distinct differences in structure, gene expression, and metabolite concentrations compared to healthy motor neurons, but that ropinirole treatment decreased these differences.
Specifically, motor neurons from the patients had shorter axons than healthy motor neurons, but when exposed to ropinirole they grew to a more normal length. In addition, 29 genes related to cholesterol synthesis were identified that tended to be increased in motor neurons in ALS, but their gene expressions were suppressed by the drug. Investigators have also indicated that lipid peroxide in cerebrospinal fluid would be a good marker of ropinirole response, both in vitro and clinically.
“We found a very striking correlation between a patient’s clinical response and their motor neuron response in vitro,” Morimoto says. Patients whose motor neurons responded robustly to ropinirole in vitro had much slower clinical disease progression with ropinirole treatment, whereas suboptimal responders showed much more rapid disease progression despite taking ropinirole.”
The researchers explained that this suggests that culturing and testing patient-derived induced pluripotent stem cell-derived motor neurons is a method that could be used clinically to predict how effective the drug would be in a given patient. They haven’t figured out why some patients respond better to ropinirole than others, but they think it’s probably due to genetic differences that they hope to identify in future research.
The study findings are encouraging because of the urgent need to find new therapies against ALS, but experts are cautious because it is a very small trial and whose results need to be confirmed. Thus, Michael Swash, Professor of Neurology at Barts and London School of Medicine (United Kingdom), has pointed out in statements to SMC Spain: “For a long time, attempts have been made to find a drug available on the market and applicable to the treatment of ALS. Ropinirole may be one of those drugs. But it is necessary to better understand its mechanism of action in order to apply it more widely. Furthermore, a larger study is required to understand who might benefit and what might be the limits of practical therapy in the use of ropinirole in ALS.”
And he adds: “More data is also needed on possible unwanted effects. There are interesting parallels in the accumulation of proteins in the neuronal cytosol between Parkinson’s disease and ALS that should be explored.”
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