Sky Pharma
Reshaping Drug Discovery: Target. Map. Treat.

When working on a landmark study that identified the target of thalidomide teratogen, a key factor in congenital disabilities, Hideki Ando made a startling discovery.

By controlling the growth of zebrafish pectoral fins—similar to human upper limbs—with targeted drugs and protein applications, he provided compelling evidence that delivering compounds directly to specific regions is the definitive way to decode drug effects on the organism.

The insight inspired Ando to establish Sky Pharma and lead the next wave of medical advancement in drug discovery and regenerative medicine.

At the crossroads of developmental engineering and drug discovery, Sky Pharma is changing the rules of therapeutic innovation with its pioneering Zebrafish Fate Map Injection Technology (Z-FIT)—a revolutionary screening platform that enables researchers to observe molecular influence in unprecedented detail.

“Our Z-FIT technology provides a high-resolution window into biological development, allowing precise mapping of molecular influence and restructuring how we discover and refine life-saving treatments,” says Ando.

He also adds, “Embryonic morphogenesis and adult regeneration often share common stem cell activation mechanisms during their processes. In other words, by screening drugs that promote tissue proliferation during embryonic development, we can identify common drug targets for regenerative medicine.”

But why use a Zebrafish?

While mice and rats are common choices for studying human diseases, they come with limitations—high costs, slow reproduction and ethical concerns. Zebrafish, on the other hand, offer a powerful alternative. Their transparent embryos allow real-time observation of drug effects at a cellular level and their rapid development accelerates research timelines.

Phenotypic screening is also highly effective for finding new drug candidates against unknown targets. In particular, zebrafish share 82 percent of their disease targets with humans, and more than 10 types of new small-molecule drug candidates that were effective in zebrafish are currently in clinical trials.

This makes zebrafish an invaluable model for researchers to quickly identify compounds and pinpoint effective treatments more precisely in actual biological conditions.

Pinpointing Potential: The Z-FIT Formula

The brilliance of Z-FIT lies in its ability to resolve the adversities that often plague traditional phenotypic screening. While phenotypic screening has long been acclaimed as a promising means for discovering novel drugs—especially when targets are unknown—these methods have significant drawbacks.

For instance, the standard “drug bath” technique immerses the entire zebrafish in a compound solution, leading to inconsistent drug penetration into the body and isolating the primary therapeutic effect from the myriads of off-target responses. In other words, it’s a false negative, where effective drugs might be overlooked simply because they aren’t absorbed adequately, while the risks of underestimating toxicity and escalating costs loom large.

Sky Pharma’s Z-FIT and high-resolution drug screening tech sidesteps these issues. It locally injects measured doses of compounds directly into target tissues, ensuring that therapeutic effects aren’t lost in translation. With this precision, Z-FIT eliminates guesswork and dramatically reduces the margin for error, laying the groundwork for regenerative medicine.

The results speak for themselves. Nearly every hit identified via Z-FIT has shown promising therapeutic effects in rodent disease models, validating its potential.

Small Molecules, Big Impact

Regenerative medicine holds the promise of repairing damaged tissues and reversing diseases, yet many approaches rely on complex and costly biological preparations. Sky Pharma is taking a different path with Z-FIT. It aims to develop regenerative medicine products using low-molecular-weight compounds.

Historically, small molecules have driven medical breakthroughs with their robustness and mass-producibility. Today, they hold potential in regenerative medicine, especially in areas like cell reprogramming.

Yet, a challenge has persisted. While small molecules can reprogram cells in Petri dishes, replicating those effects in living organisms has proven far more elusive. Z-FIT changes that, too, by accurately assessing small-molecule efficacy in vivo and ensuring only compounds with genuine therapeutic outcomes are pursued.

The approach heralds a new era of regenerative treatments that are cost-effective and reliable, easier to manufacture and simpler to store compared to traditional cell, nucleic acid and protein therapies.

Collaboration for Clinical Breakthroughs

Bringing Z-FIT from concept to reality takes more than assembling hardware. It requires an integrated research ecosystem where developmental biologists, analytical chemists and imaging specialists work hand in hand to analyze gene and protein expression changes through microinjection, quantitatively and qualitatively.

Equally essential is a high-performance laser confocal microscope, indispensable for capturing high-resolution images of tissue regeneration.

To meet these demands, Sky Pharma has joined forces with Tohoku University. This joint research agreement has been key to Sky Pharma’s progress, enabling sophisticated analyses that would have been nearly impossible without the critical support from Professor Junichi Nakai and the dedicated team at the university.

As a venture-driven company without its own production line, Sky Pharma must navigate the critical transition from discovery to large-scale preclinical trials. Its lead compound for spinal cord repair presents both immense promise and an immediate need for funding to advance toward clinical trials.

To bridge this gap, it is actively seeking venture capital investment and inviting partners to join in on this frontier to meet the needs of hundreds of millions of patients worldwide.

Mapping Molecular Marvels

To date, studies conducted worldwide have identified more than 10 new small-molecule drug candidates identified through zebrafish screening are currently in clinical trials. In Sky Pharma, for retinal diseases like glaucoma, it is screening for hits that activate retinal tissue growth by injecting compound solutions into the developing optic vesicle, the precursor to the eye. There are several compounds already approved for the treatment of other diseases that have strong retinal growth-promoting activity. These will be promising candidates for future drug repositioning.

In another breakthrough, Sky Pharma identified three compounds that stimulate spinal cord tissue growth. In one recent spinal cord injury screening, a small amount of a compound solution mixed with a tracer dye was injected into the embryonic region that will develop into the zebrafish spinal cord, following the precise Z-FIT methodology. The tracer confirmed delivery exclusively to the developing spinal cord, allowing researchers to identify compounds that activated the proliferation and differentiation of nerve and glial cells, beyond normal levels. Instead of merely counting cells, the increase in expression of markers for neural stem cells, mitotic cells, differentiated neurons and glial cells was carefully evaluated.

Hits obtained through this method were then rigorously tested in spinal cord-injured rats, where intrathecal administration consistently verified significant improvements in motor function. Although the number of hits was small, every candidate demonstrated robust functional recovery.

Equally compelling are Sky Pharma’s strides in combating dementia. By combining two hit compounds that stimulate the growth of neural stem cells and differentiated neurons, researchers achieved dramatic enhancements in short-term memory in a mouse model of dementia. With an estimated 60 million patients affected globally, this innovation could herald a new era in dementia treatment.

Sky Pharma has also discovered a compound that increases pancreatic beta cell proliferation and insulin expression, and it is developing treatment strategies for nearly 500 million diabetes patients worldwide.

The Dawn of Regenerative Ingenuity

The choice to base Sky Pharma in Sendai City, within Japan’s resilient Tohoku region, carries deep symbolic significance. The devastation wrought by the Great East Japan Earthquake of 2011 left an indelible mark on the region. By establishing its roots here, Sky Pharma commits to advancing regenerative medicine and contributing to the economic recovery and prosperity of Tohoku.

The groundbreaking discovery of Cereblon—the target responsible for thalidomide’s teratogenicity—ultimately paved the way for administering a drug directly to the target area, allowing for the much-needed efficacy evaluation.

This method, though demanding technical expertise and a deep understanding of embryology, promises precision. Such breakthrough work earned Ando, the Seiichi Tejima Research Award for the ‘Identification of a Primary Target of Thalidomide Teratogenicity.’

Sky Pharma’s story is a masterclass in rethinking the fundamentals of drug discovery. It is a narrative of radical innovation, where the delicate precision of zebrafish injections offers a glimpse into the future of regenerative medicine.

This is not merely another chapter in drug discovery nor a tale of big pharma playing catch-up. It is the dawn of scientific ingenuity and the bold ambition to develop treatments for conditions that have long defied remedy.