SCYNAPSIS
#neurosciences
#neurosciences
#neurosciences
Image credit by Satoru Morimoto / Department of Physiology, Keio University School of Medicine, Tokyo
Image credit by Satoru Morimoto / Department of Physiology, Keio University School of Medicine, Tokyo
Image credit by Satoru Morimoto / Department of Physiology, Keio University School of Medicine, Tokyo
Pablo Avalos Prado
Pablo Avalos Prado
Pablo Avalos Prado
Neuroscientist & Medical Writer
Neuroscientist & Medical Writer
Neuroscientist & Medical Writer
June 5, 2023
June 5, 2023
June 5, 2023
Ropinirole reduces ALS progression in sporadic patients in a phase-I/II clinical trial
Ropinirole reduces ALS progression in sporadic patients in a phase-I/II clinical trial
Ropinirole reduces ALS progression in sporadic patients in a phase-I/II clinical trial
A phase-I/II clinical trial reveals that ropinirole, a drug used for Parkinson treatment, is effective to reduce ALS progression in sporadic patients.
Amyotrophic lateral sclerosis (ALS) is a degenerative disorder marked by a gradual loss of motor neuron function, leading to a progressive paralysis and weakening of muscle. Typically originating in the lower extremities or hands, the disease progressively affects various body regions, ultimately necessitating assisted breathing support in the later stages. On average, patients diagnosed with ALS can expect a lifespan of three to five years after the initial onset of symptoms. A recent phase-I/II clinical trial in human patients has just demonstrated that ropinirole, a drug commonly used for treating Parkinson, might be effective to treat ALS in sporadic patients with no family history of the disease.
Ropinirole, a Parkinson treatment used to reduce progression in ALS patients
The potential benefits of this drug were already observed in a preclinical study using induced pluripotent stem cells (iPSCs), a cell lineage widely used for drug screening due to their ability to be transformed in any kind of cell. The researchers observed that ropinirole prevented cell death and neurite regression in more than 70 % of in vitro iPSCs-transformed motor neuron cells obtained from sporadic ALS patients, making this drug a potential candidate to treat these patients.
Five years later, the journal Cell Stem Cell has just published the results of a phase-I/II clinical trial that involved 20 sporadic ALS patients that followed either a placebo or ropinirole treatment.
During the first 24 weeks, the study was doubled-masked (neither the patients nor the doctors knew the treatment followed by the participants) and no differences were observed between the two groups in the ALS functional rating scale that measures the progression of the disease in aspects like mobility, activity and pulmonary function.
Nevertheless, in the last 24 next weeks of the trial all the patients started to take ropinirole - except one who continued the placebo treatment - and the scale revealed a delay in the disease progression of 28 months at the end of the trial.
However, the patients initially allocated in the placebo group and who started taking the drug after 24 weeks did not improve as much as the original group that completed 48 weeks of ropinirole therapy. This suggests that the treatment is effective when it starts at the early stages of the disease.
In addition, this clinical trial also identified biomarkers that may be used to assess the efficacy of ropinirole against ALS. In particular, cerebrospinal fluid (CF) lipid peroxide levels significantly decreased in patients assigned to the drug and who also experience important drops in neurofilament light polypeptide levels (a marker commonly used to measure neuronal damage) and in the ALS functional rating scale. Therefore, CF lipid peroxide emerges as a potential biomarker for ropinirole anti-ALS activity.
How does ropinirole work?
Although the mechanism of action of ropinirole remains unclear, the authors suggest two different models underlying ALS improvement in patients. The first mechanism concerns the activation of dopamine receptor 2 (D2R) in motor neurons, which would prevent their over activation (or hyperexcitability). The second would be the prevention of neuronal damage by mitochondrial reactive oxygen species, a group of molecules released by the motor neurons themselves that trigger cellular death.
Interestingly, the authors of the study found a set of genes involved in cholesterol generation that were upregulated in motor neurons of ALS patients, suggesting that cholesterol produced in excess by these neurons may lead to neurotoxicity, a discovery supported by other works. As a matter of fact, ropinirole also inhibited the messenger RNA involved in cholesterol generation in motor neurons in vivo. The authors conclude suggesting that down regulation of cholesterol production at the neuronal level, may be an effective treatment for ALS.
Further research is needed to support the use ropinirole for ALS treatment
Nevertheless, in spite of this promising data, the authors underline the limitations of this work: a small sample (20 individuals), the disbalanced ratio of ropinirole vs. placebo patients (specially during the open-label period) and the remarkable drop-out of patients during the study, attributable to Covid-19 outbreak and the death of some of them because of the lethality of this disease. Also, the fact that most of the significant results were obtained from the open-label phase of the study and not from the double-blind makes necessary a stronger trial supporting these preliminary data.
Original article
A phase-I/II clinical trial reveals that ropinirole, a drug used for Parkinson treatment, is effective to reduce ALS progression in sporadic patients.
Amyotrophic lateral sclerosis (ALS) is a degenerative disorder marked by a gradual loss of motor neuron function, leading to a progressive paralysis and weakening of muscle. Typically originating in the lower extremities or hands, the disease progressively affects various body regions, ultimately necessitating assisted breathing support in the later stages. On average, patients diagnosed with ALS can expect a lifespan of three to five years after the initial onset of symptoms. A recent phase-I/II clinical trial in human patients has just demonstrated that ropinirole, a drug commonly used for treating Parkinson, might be effective to treat ALS in sporadic patients with no family history of the disease.
Ropinirole, a Parkinson treatment used to reduce progression in ALS patients
The potential benefits of this drug were already observed in a preclinical study using induced pluripotent stem cells (iPSCs), a cell lineage widely used for drug screening due to their ability to be transformed in any kind of cell. The researchers observed that ropinirole prevented cell death and neurite regression in more than 70 % of in vitro iPSCs-transformed motor neuron cells obtained from sporadic ALS patients, making this drug a potential candidate to treat these patients.
Five years later, the journal Cell Stem Cell has just published the results of a phase-I/II clinical trial that involved 20 sporadic ALS patients that followed either a placebo or ropinirole treatment.
During the first 24 weeks, the study was doubled-masked (neither the patients nor the doctors knew the treatment followed by the participants) and no differences were observed between the two groups in the ALS functional rating scale that measures the progression of the disease in aspects like mobility, activity and pulmonary function.
Nevertheless, in the last 24 next weeks of the trial all the patients started to take ropinirole - except one who continued the placebo treatment - and the scale revealed a delay in the disease progression of 28 months at the end of the trial.
However, the patients initially allocated in the placebo group and who started taking the drug after 24 weeks did not improve as much as the original group that completed 48 weeks of ropinirole therapy. This suggests that the treatment is effective when it starts at the early stages of the disease.
In addition, this clinical trial also identified biomarkers that may be used to assess the efficacy of ropinirole against ALS. In particular, cerebrospinal fluid (CF) lipid peroxide levels significantly decreased in patients assigned to the drug and who also experience important drops in neurofilament light polypeptide levels (a marker commonly used to measure neuronal damage) and in the ALS functional rating scale. Therefore, CF lipid peroxide emerges as a potential biomarker for ropinirole anti-ALS activity.
How does ropinirole work?
Although the mechanism of action of ropinirole remains unclear, the authors suggest two different models underlying ALS improvement in patients. The first mechanism concerns the activation of dopamine receptor 2 (D2R) in motor neurons, which would prevent their over activation (or hyperexcitability). The second would be the prevention of neuronal damage by mitochondrial reactive oxygen species, a group of molecules released by the motor neurons themselves that trigger cellular death.
Interestingly, the authors of the study found a set of genes involved in cholesterol generation that were upregulated in motor neurons of ALS patients, suggesting that cholesterol produced in excess by these neurons may lead to neurotoxicity, a discovery supported by other works. As a matter of fact, ropinirole also inhibited the messenger RNA involved in cholesterol generation in motor neurons in vivo. The authors conclude suggesting that down regulation of cholesterol production at the neuronal level, may be an effective treatment for ALS.
Further research is needed to support the use ropinirole for ALS treatment
Nevertheless, in spite of this promising data, the authors underline the limitations of this work: a small sample (20 individuals), the disbalanced ratio of ropinirole vs. placebo patients (specially during the open-label period) and the remarkable drop-out of patients during the study, attributable to Covid-19 outbreak and the death of some of them because of the lethality of this disease. Also, the fact that most of the significant results were obtained from the open-label phase of the study and not from the double-blind makes necessary a stronger trial supporting these preliminary data.
Original article
A phase-I/II clinical trial reveals that ropinirole, a drug used for Parkinson treatment, is effective to reduce ALS progression in sporadic patients.
Amyotrophic lateral sclerosis (ALS) is a degenerative disorder marked by a gradual loss of motor neuron function, leading to a progressive paralysis and weakening of muscle. Typically originating in the lower extremities or hands, the disease progressively affects various body regions, ultimately necessitating assisted breathing support in the later stages. On average, patients diagnosed with ALS can expect a lifespan of three to five years after the initial onset of symptoms. A recent phase-I/II clinical trial in human patients has just demonstrated that ropinirole, a drug commonly used for treating Parkinson, might be effective to treat ALS in sporadic patients with no family history of the disease.
Ropinirole, a Parkinson treatment used to reduce progression in ALS patients
The potential benefits of this drug were already observed in a preclinical study using induced pluripotent stem cells (iPSCs), a cell lineage widely used for drug screening due to their ability to be transformed in any kind of cell. The researchers observed that ropinirole prevented cell death and neurite regression in more than 70 % of in vitro iPSCs-transformed motor neuron cells obtained from sporadic ALS patients, making this drug a potential candidate to treat these patients.
Five years later, the journal Cell Stem Cell has just published the results of a phase-I/II clinical trial that involved 20 sporadic ALS patients that followed either a placebo or ropinirole treatment.
During the first 24 weeks, the study was doubled-masked (neither the patients nor the doctors knew the treatment followed by the participants) and no differences were observed between the two groups in the ALS functional rating scale that measures the progression of the disease in aspects like mobility, activity and pulmonary function.
Nevertheless, in the last 24 next weeks of the trial all the patients started to take ropinirole - except one who continued the placebo treatment - and the scale revealed a delay in the disease progression of 28 months at the end of the trial.
However, the patients initially allocated in the placebo group and who started taking the drug after 24 weeks did not improve as much as the original group that completed 48 weeks of ropinirole therapy. This suggests that the treatment is effective when it starts at the early stages of the disease.
In addition, this clinical trial also identified biomarkers that may be used to assess the efficacy of ropinirole against ALS. In particular, cerebrospinal fluid (CF) lipid peroxide levels significantly decreased in patients assigned to the drug and who also experience important drops in neurofilament light polypeptide levels (a marker commonly used to measure neuronal damage) and in the ALS functional rating scale. Therefore, CF lipid peroxide emerges as a potential biomarker for ropinirole anti-ALS activity.
How does ropinirole work?
Although the mechanism of action of ropinirole remains unclear, the authors suggest two different models underlying ALS improvement in patients. The first mechanism concerns the activation of dopamine receptor 2 (D2R) in motor neurons, which would prevent their over activation (or hyperexcitability). The second would be the prevention of neuronal damage by mitochondrial reactive oxygen species, a group of molecules released by the motor neurons themselves that trigger cellular death.
Interestingly, the authors of the study found a set of genes involved in cholesterol generation that were upregulated in motor neurons of ALS patients, suggesting that cholesterol produced in excess by these neurons may lead to neurotoxicity, a discovery supported by other works. As a matter of fact, ropinirole also inhibited the messenger RNA involved in cholesterol generation in motor neurons in vivo. The authors conclude suggesting that down regulation of cholesterol production at the neuronal level, may be an effective treatment for ALS.
Further research is needed to support the use ropinirole for ALS treatment
Nevertheless, in spite of this promising data, the authors underline the limitations of this work: a small sample (20 individuals), the disbalanced ratio of ropinirole vs. placebo patients (specially during the open-label period) and the remarkable drop-out of patients during the study, attributable to Covid-19 outbreak and the death of some of them because of the lethality of this disease. Also, the fact that most of the significant results were obtained from the open-label phase of the study and not from the double-blind makes necessary a stronger trial supporting these preliminary data.
Original article