Heraldo de Madrid - iPS Cell Research Accelerates Drug Discovery for ALS and Spinal Cord Injury

Researchers at Keiō University are utilizing induced pluripotent stem (iPS) cell technology to accelerate the development of treatments for rare and complex neurological diseases. By modeling patient-specific conditions in laboratory settings, scientists have bypassed traditional animal models that often fail to predict human responses, leading to faster identification of candidate drugs and regenerative therapies.

Okano Hideyuki, director of the Keiō University Regenerative Medicine Research Center, has pioneered methods to differentiate iPS cells into specific cell types, creating direct bridges between basic research and clinical application. His work addresses a critical gap in medical science: the fundamental differences between human and mouse neurons, which have historically caused promising drug candidates to fail during human clinical trials.

The most significant progress has occurred in the treatment of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease that destroys motor neurons while leaving consciousness intact. Approximately 10,000 people in Japan live with ALS, yet no curative treatment or reliably effective drug currently exists. For decades, researchers relied on mouse models engineered with patient-specific genetic mutations. However, more than 10 drug candidates that showed efficacy in mice proved ineffective in humans.

"Human and mouse neurons differ fundamentally in their properties and circuitry," Okano explained. "For central nervous system diseases, that gap has been a decisive barrier."

To overcome this obstacle, Okano’s team generated iPS cells from ALS patients and differentiated them into motor neurons. These human-derived cells reproduced the disease's hallmarks in laboratory dishes, including shortened neurites, hyperexcitability, and early cell death—abnormalities consistent with those observed in patients' brains and spinal cords.

Using this accurate human cell model, the team pursued drug repositioning, testing existing approved medications for new therapeutic effects. Because safety profiles are already established, repurposed drugs can reach patients more rapidly and at lower costs.

"Using human iPS cells allows us to create patient-specific cells carrying the exact mutations," Okano stated. "We can even build 3D organoids that mimic organ structure. It made sense to test drugs directly on such human-derived cells."

The strategy yielded results in 2018, when the team discovered that ropinirole hydrochloride, a medication typically used for Parkinson’s disease, significantly improved the abnormal phenotypes of ALS motor neurons. The drug restored neurite length, reduced hyperexcitability, and prevented cell death.

Following the publication of these findings in Nature Medicine, Keiō University launched a physician-initiated clinical trial that December, enrolling approximately 20 ALS patients. The results were encouraging, and preparations for subsequent trial phases are currently underway.

"The speed from iPS cell-based discovery to clinical testing would have been unthinkable under the earlier models," Okano noted.

A key advantage of this approach is its ability to account for patient-to-patient variability. Even among patients with the same ALS diagnosis, underlying pathology varies enormously. To address this diversity, Okano’s team generated iPS cells from roughly 250 ALS patients and conducted detailed analyses of each cell line’s characteristics.

The research team is now collecting multidimensional datasets, including genomic analyses, cellular phenotype evaluations, and assessments of small extracellular vesicles secreted by the cells. Okano aims to use artificial intelligence to build a system capable of recommending individualized drug treatments tailored to each patient’s biology.

Beyond drug discovery, Okano’s team is conducting regenerative medicine trials using human iPS cell-derived neural precursor cells transplanted into patients with spinal cord injuries. In a study involving four patients with severe quadriplegic paralysis, two showed marked improvement, and one regained enough function to begin walking training.

This represented the world’s first clinical study using human iPS cell-derived neural precursor cells. Okano stated that because the therapeutic effect is clear, the team hopes to secure conditional, time-limited approval within three to four years.

Japan’s 2014 revision of the Pharmaceuticals and Medical Devices Act created a pathway for the early provision of regenerative medicine products once probable efficacy and safety are demonstrated. This framework allows products to be used while additional evidence is gathered over seven years, a system considered one of the most progressive globally.

Ensuring real-world application requires reliable manufacturing technology. Okano serves as chief scientific officer of K Pharma, a biotech startup spun out of Keiō University to translate basic research into practical applications. The company is collaborating with Nikon Cell Innovation to manufacture human iPS cell-based regenerative medicine products for spinal cord injury, aiming to begin company-led clinical trials by 2027.

Okano’s work also extends to psychiatric conditions such as schizophrenia, which are difficult to study because symptoms like hallucinations require speech and cannot be observed in animals. By generating neurons from the iPS cells of patients with psychiatric disorders, researchers aim to uncover human-specific disease mechanisms.

In collaboration with Swiss-based MaxWell Biosystems, the team is analyzing the electrical activity and morphology of neurons derived from schizophrenia patients’ iPS cells using advanced measurement technologies.

"If we can identify the electrical abnormalities in these neurons and test whether drugs correct them, we may be able to move directly toward clinical application without relying on animal models," Okano said. This approach could shrink drug development timelines, which typically require 10 to 20 years, to just one or two years.

Twenty years after Yamanaka Shin’ya first developed iPS cells at Kyoto University’s Institute for Frontier Medical Sciences in 2006, the promise of transformative treatments is beginning to materialize. Yamanaka won a Nobel Prize in 2012 for this work. Okano emphasized that while iPS cell technology enables faster discovery, the real challenge remains making these therapies widely available to all patients who need them.

With Japan’s February 2026 announcement of a manufacturing system for an iPS cell-based therapy for spinal cord injury, the field is entering a new phase of real-world implementation.

K.Bravo--HdM