MSGID: 1:317/3 647ac1ee   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Parkinson's disease drug ropinirole safely slowed the progression of ALS   
   for over 6 months in a clinical trial    
      
     Date:   
         June 2, 2023   
     Source:   
         Cell Press   
     Summary:   
         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. Researchers now show in an early clinical trial   
         that the Parkinson's disease drug ropinirole is safe to use in ALS   
         patients and delayed disease progression by 27.9 weeks on average.   
      
      
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   FULL STORY   
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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. Reporting June 1   
   in the journal Cell Stem Cell, researchers from Japan show in an early   
   clinical trial that the Parkinson's disease drug ropinirole is safe to use   
   in ALS patients and delayed disease progression by 27.9 weeks on average.   
      
   Some patients were more responsive to ropinirole treatment than others,   
   and the researchers were able to predict clinical responsiveness in   
   vitro using motor neurons derived from patient stem cells.   
      
   "ALS is totally incurable, and it's a very difficult disease to treat,"   
   says senior author and physiologist Hideyuki Okano of the Keio University   
   School of Medicine in Tokyo. "We previously identified ropinirole as   
   a potential anti-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   
   that it potentially has some therapeutic effect, but to confirm its   
   effectiveness we need more studies, and we are now planning a phase 3   
   trial for the near future."  To test ropinirole's safety and effectiveness   
   in patients with sporadic (i.e., non-familial) ALS, the team recruited   
   20 patients receiving care at Keio University Hospital in Japan. None of   
   the patients carried genes predisposing to the disease, and, on average,   
   they had been living with ALS for 20 months.   
      
   The trial was double blinded for the first 24 weeks, meaning that   
   the patients and doctors did not know which patients were receiving   
   ropinirole and which were receiving a placebo. Then, for the following 24   
   weeks, all patients who wished to continue were knowingly administered   
   ropinirole. Many patients dropped out along the way -- partially due   
   to the COVID-19 pandemic -- so only 7/13 ropinirole-treated and 1/7   
   placebo-followed-by-ropinirole-treated patients were monitored for the   
   full year. However, no patients dropped out due to safety reasons.   
      
   To determine whether the drug was effective at slowing the progression   
   of ALS, the team monitored a variety of different measures throughout the   
   trial and for 4 weeks after treatment concluded. These included changes in   
   the patients' self-reported physical activity and ability to eat and drink   
   independently, activity data from wearable devices, and physician-measured   
   changes in mobility, muscle strength, and lung function.   
      
   "We found that ropinirole is safe and tolerable for ALS patients and   
   shows therapeutic promise at helping them sustain daily activity and   
   muscle strength," says first author Satoru Morimoto, a neurologist at   
   the 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 they were more likely to survive.   
      
   The benefits of ropinirole relative to the placebo became increasingly   
   pronounced as the trial progressed. However, placebo group patients who   
   began taking ropinirole halfway through the trial did not experience these   
   improvements, which suggests that ropinirole treatment may only be useful   
   if treatment is started earlier and administered over a longer duration.   
      
   Next, the researchers 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   
   grew these cells into motor neurons in the lab. Compared to healthy motor   
   neurons, they found that motor neurons from ALS patients showed distinct   
   differences in structure, gene expression, and metabolite concentrations,   
   but ropinirole treatment reduced these differences.   
      
   Specifically, motor neurons grown 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   
   upregulated in motor neurons from ALS patients, but ropinirole treatment   
   suppressed their gene expressions over time. They also identified   
   lipid peroxide as a good surrogate marker for estimating 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 vitro," says   
   Morimoto. "Patients whose motor neurons responded robustly to ropinirole   
   in vitro had a much slower clinical disease progression with ropinirole   
   treatment, while suboptimal responders showed much more rapid disease   
   progression despite taking ropinirole."  The researchers say that 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's unclear why some patients are more responsive to ropinirole   
   than others, but the researchers think that it's probably due to genetic   
   differences that they hope to pinpoint in future studies.   
      
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                   # Patient_Education_and_Counseling # Today's_Healthcare #   
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                   Multiple_Sclerosis   
       * RELATED_TERMS   
             o Excitotoxicity_and_cell_damage o Palliative_care   
             o Alzheimer's_disease o Multiple_sclerosis o   
             Bovine_spongiform_encephalopathy o Parkinson's_disease o   
             Delirium o Deep_brain_stimulation   
      
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   Story Source: Materials provided by Cell_Press. Note: Content may be   
   edited for style and length.   
      
      
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   Journal Reference:   
      1. Satoru Morimoto, Shinichi Takahashi, Daisuke Ito, Yugaku Date',   
      Kensuke   
         Okada, Chris Kato, Shiho Nakamura, Fumiko Ozawa, Chai Muh Chyi,   
         Ayumi Nishiyama, Naoki Suzuki, Koki Fujimori, Tosho Kondo, Masaki   
         Takao, Miwa Hirai, Yasuaki Kabe, Makoto Suematsu, Masahiro Jinzaki,   
         Masashi Aoki, Yuto Fujiki, Yasunori Sato, Norihiro Suzuki, Jin   
         Nakahara, Hideyuki Okano. Phase 1/2a clinical trial in ALS with   
         ropinirole, a drug candidate identified by iPSC drug discovery. Cell   
         Stem Cell, 2023; 30 (6): 766 DOI: 10.1016/j.stem.2023.04.017   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/06/230602115106.htm   
      
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