How ALS Cell Models That Began In Blood Spurred An Encouraging Early-Stage Clinical Trial

NEW YORK – It started with blood.

An early-stage clinical trial suggests a Parkinson’s disease drug is safe and may slow symptom progression for individuals with some forms of amyotrophic lateral sclerosis (ALS) — results made possible by prior research on patient-specific motor neurons made from immune cells in the blood via a series of cellular reprogramming steps.

For their phase 1/2a “ropinirole hydrochloride remedy for ALS” (ROPALS) trial, researchers at Keio University School of Medicine in Tokyo and elsewhere looked at the safety and effectiveness of a drug called ropinirole hydrochloride in individuals with sporadic ALS.

The drug was flagged in a 2018 study published in the journal Nature Medicine. There, some members of the same team tested more than 1,200 approved drugs on motor neuron cells from individuals with various forms of ALS — including sporadic ALS cases and cases linked to specific genetic mutations — in an effort to find drugs that would curb the detrimental effects of the disease.

But, not surprisingly, they didn’t use motor neurons extracted directly from the patients.

Instead, the team started with cell lines based on a type of adaptive immune cell in the blood. Though the cells reflected the genetics of the ALS blood donors, they offered a rather limited window into what was going on in central nervous system cells being walloped by ALS.

So investigators went a few steps further, reprogramming the cells to become stem cell-like “induced pluripotent stem cells” — which were then coaxed to specialize into motor neurons in the lab.

While they did see variation in the degeneration patterns, disease features, and drug responses detected across this set of motor neuron models, investigators involved in the 2018 study described dozens of drugs that appeared to curtail ALS-related features in specific clusters of cells.

One potential treatment stood out in cells originating from 32 individuals with sporadic ALS: a Parkinson’s disease drug called ropinirole, known for activating a receptor for the pleasure-sensing hormone dopamine.

After a series of follow-up experiments aimed at understanding this effect more clearly, members of the team set out to test ropinirole in 20 individuals with sporadic ALS in the ROPALS trial. In addition to tracking adverse events, investigators secondarily scrutinized the drug’s potential effects on patients’ functional abilities.

“To the best of our knowledge, the ROPALS trial is the representative touchstone of [induced pluripotent stem cell (iPSC)]-based drug repurposing-enabled trials to define the feasibility of iPSC models in predicting clinical outcomes and replacing failure-prone preclinical transgenic mouse models of ALS,” senior and corresponding author Hideyuki Okano, a physiology researcher at Keio University School of Medicine, and his colleagues wrote in a recent Cell Stem Cell paper outlining the ROPALS clinical trial design and results.

During the double-blind portion of the trial, 13 individuals with ALS were randomized to receive the drug, while seven ALS patients received a placebo. In an “open-label” extension period, meanwhile, all patients had the option of receiving ropinirole for another four to 24 weeks.

Over the first 24 weeks of the study, when patients did not know if they were getting ropinirole or placebo, the investigators saw a similar adverse event patterns and functional declines in both the test and control arms of the trial, though individuals in both groups appeared to maintain their daily activity patterns and muscle strength.

One patient in the treatment arm experienced ALS progression during that stage of the study and one patient in the placebo group died. Of the six patients who completed placebo treatment, five continued on the drug in the open-label period, as did all 12 patients from the initial treatment arm.

The team noted that functional declines were curbed significantly in the individuals taking ropinirole during the open-label stage of the study. These individuals also went nearly 28 weeks longer without symptom progression, on average.

Despite the promising data, the ROPALS trial results represent a very early stage on the path to producing a new, approved treatment for ALS.

And authors of the Cell Stem Cell study highlighted the low success rates that have plagued drug development efforts in ALS and other nervous system diseases. Drugs showing potential activity in preclinical models often fail to pan out, and even drug candidates that reach advanced clinical trials can fall short.

In a phase 3 clinical trial reported nearly a decade ago, for example, researchers from Biogen, Massachusetts General Hospital, and other centers found that a drug called dexpramipexole failed to outperform the placebo when it came to boosting survival or improving function for individuals with ALS, despite encouraging data in earlier-stage trials.

Still, the ropinirole results so far point to the potential of pursuing treatments based on their effects in motor neuron cells that originated in actual ALS patients, rather than relying on more indirect approaches such as animal models.

In a related commentary article in Cell Stem Cell, University of Eastern Piedmont researchers Letizia Mazzini and Fabiola De Marchi, who were not involved in the new research, noted that induced pluripotent stem cell-based models “can have several advantages, such as reducing trial errors and trial failure, reducing costs for the healthcare system, and enabling a better patient selection.”

Though the Italian researchers emphasized that “critical issues must be resolved before this technology can enter multi-center clinical trial design,” they noted that the use of induced pluripotent stem cells, combined with genomic strategies for understanding and tracking disease, may together point the way toward patient-tailored ALS treatments.