ALS Breakthrough – Parkinson’s Drug Safely Slows Disease Progression by Over 6 Months

ALS Breakthrough: Parkinson’s Drug Slows Disease Progression by Over 6 Months

Scientists have made a significant advancement in the treatment of amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig’s disease. ALS is a fatal neurological disorder characterized by the gradual loss of muscle control, and there is currently no cure. However, a recent early-stage clinical trial, featured in the journal Cell Stem Cell, has shown promising results with the drug ropinirole, typically used for Parkinson’s disease. The trial demonstrated that ropinirole is safe for ALS patients and can delay the progression of the disease by an average of 27.9 weeks.

Interestingly, some patients responded better to ropinirole treatment than others. In the laboratory, scientists were able to predict this clinical responsiveness by using motor neurons derived from the stem cells of ALS patients.

Dr. Hideyuki Okano, a senior author and physiologist at Keio University School of Medicine in Tokyo, explains, “ALS is an incurable and challenging disease to treat. We previously identified ropinirole as a potential anti-ALS drug in vitro through iPSC drug discovery. With this trial, we have demonstrated its safety and potential therapeutic effects. However, further studies are needed to confirm its effectiveness. We are planning a phase 3 trial in the near future.”

For the trial, researchers recruited 20 ALS patients without familial genetic predisposition to the disease who had been living with ALS for an average of 20 months. The trial was conducted in a double-blind manner for the first 24 weeks, where neither the patients nor the doctors knew who received ropinirole or a placebo. In the following 24 weeks, all patients who wished to continue were knowingly given ropinirole. Some patients dropped out during the trial, partly due to the COVID-19 pandemic, resulting in 7 out of 13 ropinirole-treated and 1 out of 7 placebo-followed-by-ropinirole-treated patients being monitored for the full year. Importantly, no patients dropped out due to safety concerns.

To assess the drug’s effectiveness in slowing ALS progression, the researchers monitored various measures throughout the trial and for 4 weeks after the treatment ended. These measures included self-reported physical activity, independent eating and drinking ability, wearable device data, as well as changes in mobility, muscle strength, and lung function as measured by physicians.

Dr. Satoru Morimoto, a neurologist at Keio University School of Medicine and the first author of the study, reports, “We found that ropinirole is safe and well-tolerated by ALS patients and shows promise in sustaining daily activity and muscle strength.”

Patients who received ropinirole throughout the trial demonstrated higher levels of physical activity compared to the placebo group. They also exhibited slower declines in mobility, muscle strength, lung function, and had a higher likelihood of survival.

The benefits of ropinirole became more pronounced as the trial progressed. However, patients in the placebo group who started taking ropinirole midway did not experience the same improvements. This suggests that ropinirole treatment may be most effective when initiated early and administered for an extended period.

The researchers delved into the mechanisms underlying ropinirole’s effects and searched for molecular markers of the disease. They generated induced pluripotent stem cells from the patients’ blood and cultivated them into motor neurons in the lab. Comparing these motor neurons to healthy ones, they discovered distinct differences in structure, gene expression, and metabolite concentrations in ALS patients’ motor neurons. However, treatment with ropinirole reduced these differences.

In particular, motor neurons derived from ALS patients exhibited shorter neurites than healthy motor neurons. Yet, when treated with ropinirole, the axons grew to a more normal length. The researchers also identified 29 genes associated with cholesterol synthesis that were upregulated in motor neurons from ALS patients. However, ropinirole treatment suppressed the expression of these genes over time. They also identified lipid peroxide as a reliable surrogate marker for estimating the effectiveness of ropinirole, both in vitro and clinically.

Dr. Morimoto states, “We observed a remarkable correlation between a patient’s clinical response and their motor neurons’ response to ropinirole in vitro. Patients whose motor neurons exhibited robust responses to ropinirole had slower disease progression with the drug, while those with suboptimal responses experienced faster disease progression despite taking ropinirole.”

The researchers believe that this approach of growing and testing motor neurons from induced pluripotent stem cells derived from ALS patients could be used clinically to predict the drug’s effectiveness for individual patients. While the reasons behind varying patient responses to ropinirole remain unclear, the researchers hope to identify genetic differences through future studies.

This research received support from various funding sources, including the Japan Agency for Medical Research and Development (AMED), the Japan Society for the Promotion of Science (JSPS), and the Uehara Memorial Foundation, among others. GlaxoSmithKline supplied the study drug.

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More about ALS breakthrough

• Cell Stem Cell journal article
• ALS Association
• Parkinson’s Foundation
• Japan Agency for Medical Research and Development (AMED)
• Japan Society for the Promotion of Science (JSPS)