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 ========================================================================== 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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========================================================================== Story Source: Materials provided by Cell_Press. Note: Content may be
edited for style and length.


========================================================================== 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 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/06/230602115106.htm

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