In amyotrophic lateral sclerosis (ALS), the motor nerve cells are gradually lost, so that those affected can move less and less and eventually die. So far, the disease cannot be cured and can hardly be treated. In a clinical feasibility study, researchers have now investigated whether a drug that has long been used to treat Parkinson's can also slow the progression of ALS. Although efficacy against ALS is unclear due to the small number of subjects, the study points to possible mechanisms of action and suggests that the drug also has a favorable safety profile in ALS patients. Larger studies are to follow.
Amyotrophic lateral sclerosis (ALS) is a degenerative disease of nerve tissue that leads to progressive muscle paralysis. So far, the disease cannot be cured and there are no causal treatments. Current therapies can only slow the progression of the disease to a small extent and focus on relieving the symptoms. A problem in the research of new drugs is that the results from animal models for neurological diseases can only be transferred to humans to a limited extent.
Evidence from cell cultures
A team led by Satoru Morimoto from the Keio University School of Medicine in Tokyo therefore used a different approach: Instead of relying on animal models, they used induced pluripotent stem cells from ALS patients and used them to grow motor neurons, i.e. exactly the nerve cells that control muscle activity control and who are harmed by the disease. They tested various active ingredients on these and found that a drug called ropinirole, which is already being used successfully against Parkinson's disease, slowed down the damage to motor neurons, at least in the laboratory. Ropinirole is a so-called dopamine agonist, which binds to the same receptors as the messenger substance dopamine.
To test the drug's safety and effectiveness in ALS patients, Morimoto and his team conducted a clinical proof of concept study with a small number of subjects. Thirteen people who had had ALS for an average of 20 months received ropinirole and seven people received a placebo. In the first six months of the study, neither the doctors nor the patients knew who was receiving the real drug and who was receiving the dummy drug. The research team paid attention to possible side effects and also assessed the patient's condition using an evaluation scale that records, among other things, how well the person can move, how they can manage in everyday life, and to what extent they can speak and breathe.
Good safety, questionable effectiveness
Looking at side effects, the team found that ropinirole had a favorable safety profile in ALS patients. Although patients from the Rpoinirol group reported problems such as constipation, nausea and headaches somewhat more frequently, there were no serious side effects. "We have found that ropinirole is safe and tolerable for ALS patients," said Morimoto. In terms of efficacy, the results were less promising: "During the double-blind phase of the study, subjects maintained muscle strength and daily activity, but the score used to assess the functional status of ALS patients deteriorated in all subjects ' said the research team. "It made no difference whether a patient had received the drug or a placebo."
After the blinded phase, however, the team continued the study, with the subjects from the placebo group now also receiving ropinirole. During this phase, patients who were initially given ropinirole got worse at a slightly slower rate than those who were initially given placebo. However, the significance of the results is still very limited. Because many patients dropped out of the study - partly because their disease had progressed too far, partly because of other factors such as Covid-19 - only eight patients completed the full study, including just one from the original placebo group. "To confirm the effectiveness, we need further studies and are now planning a phase 3 study for the near future," says Morimoto's colleague Hideyuki Okano.
Possible marker for individual response
In search of possible mechanisms of action, the research team also generated induced pluripotent stem cells from the blood of the study participants and cultivated them into motor neurons. Studies of these ALS motoneurons revealed numerous differences to healthy motoneurons: Among other things, 29 genes associated with the synthesis of cholesterol were upregulated in the ALS motoneurons. Treatment with ropinirole suppressed this excessive gene expression. She also ensured that shortened axons of the nerve cells grew to a normal length.
The motor neurons of different patients did not all respond equally well to the drug. However, the researchers were able to use the concentration of lipid peroxide in the cells to predict how well the drug would work, both in cell cultures and in living patients. "We found a very striking correlation between a patient's clinical response and the response of their motor neurons in vitro," says Morimoto. "Patients whose motor neurons were highly responsive to ropinirole in vitro had a much slower clinical progression of the disease with ropinirole treatment." of a treatment to find out which patients can particularly benefit from it.
Source: Satoru Morimoto (Keio University School of Medicine, Tokyo, Japan) et al., Cell Stem Cell, doi: 10.1016/j.stem.2023.04.017