Can Parkinson’s disease drug delay ALS progression?
ALS is an incurable disease that causes the gradual loss of muscle control. Researchers from Japan have shown that the Parkinson’s disease drug ropinirole may delay disease progression in ALS patients. The early clinical trial showed that the drug is safe to use and has a potential therapeutic effect. However, to confirm its efficacy, phase 3 trials are needed.
The Study
To test ropinirole’s safety and efficacy in nonfamilial ALS patients, the team recruited 20 patients receiving care at Keio University. For the first 24 weeks, the trial was double-blind, and then it was single-blind for the next 24 weeks. Patients who received ropinirole during both phases of the trial were more physically active than patients in the placebo group. They also showed slower rates of decline in mobility, muscle strength, and lung function, and were more likely to survive.
The Potential of Ropinirole
The benefits of ropinirole relative to placebo became increasingly pronounced as the trial progressed. However, patients in the placebo group who started ropinirole halfway through the trial did not experience these improvements, indicating that ropinirole’s treatment may only be useful if it is given for a longer duration and started earlier.
Patient-Derived Induced Pluripotent Stem Cells
To investigate the mechanisms behind ropinirole’s effects, researchers generated induced pluripotent stem cells from patient blood and turned them into motor neurons in the laboratory. Motor neurons from ALS patients showed clear differences in structure, gene expression, and metabolite concentrations, but ropinirole treatment reduced these differences. Motor neurons that grew from ALS patients had shorter neurites compared to healthy motor neurons, but these axons grew to a more normal length when the cells were treated with ropinirole.
Predicting the Effectiveness of the Drug
The researchers found a strong correlation between a patient’s clinical response and the response of their motor neurons in vitro. Patients whose motor neurons responded strongly to ropinirole in vitro had slower clinical disease progression with ropinirole treatment. Whereas suboptimal responders had much more rapid disease progression despite taking ropinirole. This suggests that this method of growing and testing motor neurons from patient-derived induced pluripotent stem cells could be clinically used to predict how effective the drug would be for a given patient.
Summary
The Parkinson’s disease drug ropinirole shows promise in delaying ALS disease progression. Researchers found that ropinirole is safe and tolerable for ALS patients. Patients who received ropinirole during both phases of the trial were more physically active than patients in the placebo group. They also showed slower rates of decline in mobility, muscle strength, and lung function, and were more likely to survive. This study suggests that the method of growing and testing motor neurons from patient-derived induced pluripotent stem cells could predict the effectiveness of the drug for a given patient.
ALS remains a devastating disease, with an average life expectancy of three to five years after diagnosis. Ropinirole may provide some hope to those suffering from the disease. The next step is to conduct phase 3 trials to confirm the drug’s efficacy. Meanwhile, scientists continue to investigate ALS to understand the disease better and develop new treatments.
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Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a fatal motor neuron disease that causes people to gradually lose control of their muscles. There is no cure, and current treatments focus on reducing symptoms and providing supportive care. Report of June 1 in the newspaper. Cell Stem CellResearchers from Japan show in an early clinical trial that the Parkinson’s disease drug ropinirole is safe to use in ALS patients and delays disease progression by an average of 27.9 weeks.
Some patients responded more to ropinirole treatment than others, and the investigators were able to predict the clinical response. in vitro using motor neurons derived from patient stem cells.
“ALS is completely incurable and is a very difficult disease to treat,” says lead author and physiologist Hideyuki Okano of Keio University School of Medicine in Tokyo. “We previously identified ropinirole as a potential ALS drug in vitro by iPSC drug discovery, and with this trial, we have shown that it is safe to use in ALS patients and potentially has some therapeutic effect, but to confirm its efficacy we need more studies, and now we are planning a phase 3 trial to The near future”.
To test the safety and efficacy of ropinirole in patients with sporadic (ie, nonfamilial) ALS, the team recruited 20 patients receiving care at Keio University Hospital in Japan. None of the patients carried genes that predisposed to the disease and, on average, had lived with ALS for 20 months.
The trial was double-blind for the first 24 weeks, meaning that patients and physicians did not know which patients received ropinirole and which received a placebo. Then, for the next 24 weeks, all patients who wanted to continue were knowingly given ropinirole. Many patients dropped out along the way, partly due to the COVID-19 pandemic, so only 7/13 ropinirole-treated patients and 1/7 placebo-treated patients followed by ropinirole were monitored throughout the year. However, no patient dropped out for safety reasons.
To determine if the drug was effective in slowing the progression of ALS, the team monitored a variety of different measures throughout the trial and for 4 weeks after treatment ended. These included changes in patients’ physical activity and ability to eat and drink independently, activity data from wearable devices, and clinician-measured changes in mobility, muscle strength, and lung function.
“We found that ropinirole is safe and tolerable for ALS patients and shows therapeutic promise in helping them maintain daily activity and muscle strength,” says first author Satoru Morimoto, a neurologist at Keio University School of Medicine. in Tokyo.
Patients who received ropinirole during both phases of the trial were more physically active than patients in the placebo group. They also showed slower rates of decline in mobility, muscle strength, and lung function, and were more likely to survive.
The benefits of ropinirole relative to placebo became increasingly pronounced as the trial progressed. However, patients in the placebo group who started ropinirole halfway through the trial did not experience these improvements, suggesting that ropinirole treatment may only be useful if treatment is started earlier and is given for a longer duration.
The researchers then investigated the mechanisms behind ropinirole’s effects and looked for molecular markers of the disease. To do this, they generated induced pluripotent stem cells from the patients’ blood and turned these cells into motor neurons in the laboratory. Compared with healthy motor neurons, they found that motor neurons from ALS patients showed clear differences in structure, gene expression, and metabolite concentrations, but ropinirole treatment reduced these differences.
Specifically, motor neurons that grew from ALS patients had shorter neurites compared to healthy motor neurons, but these axons grew to a more normal length when the cells were treated with ropinirole. The team also identified 29 genes related to cholesterol synthesis that tended to be increased in the motor neurons of ALS patients, but ropinirole treatment suppressed their gene expressions over time. They also identified lipid peroxide as a good surrogate marker to estimate the effect of ropinirole 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 vitrosays Morimoto. “Patients whose motor neurons responded strongly to ropinirole in vitro had much slower clinical disease progression with ropinirole treatment, whereas suboptimal responders had much more rapid disease progression despite taking ropinirole.”
The researchers say this suggests that this method of growing and testing motor neurons from patient-derived induced pluripotent stem cells could be used clinically to predict how effective the drug would be for a given patient. It is not clear why some patients respond better to ropinirole than others, but the researchers believe it is probably due to genetic differences that they hope to identify in future studies.
https://www.sciencedaily.com/releases/2023/06/230602115106.htm
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