Scientific Groundbreakers

An interview with Klaus van Leyen, Ph.D. (MGH)

Associate Professor in Radiology, Mass General Hospital / Harvard Medical School

In 1998, as a postdoc at Memorial Sloan-Kettering Cancer Center, Klaus van Leyen started his academic career studying a critical enzyme that regulates cell organelle function in the context of red blood cell maturation – 12/15-lipoxygenase (12/15-LOX). 12/15-LOX was discovered to mediate the degradation of mitochondria, a pivotal organelle that regulates cell metabolism and survival. He conjectured that a small molecule 12/15-LOX inhibitor, treating cell death, could be a useful therapeutic.

Klaus then asked himself a couple of questions that would define his research for the next fifteen years, ‘Do we see similar phenomena in diseases, and what could those diseases possibly be’?

Klaus was a passionate young academic researcher spending his days and nights in the stacks of the Sloan-Kettering and Cornell libraries in New York City, rummaging through library archives and microfiche searching for answers to these questions. After months of research, he decided that he was interested in exploring cardiovascular disease and stroke. He didn't know it at the time, but this decision set the path for a long journey.

Klaus reminisced, “I was coming from basic academic research which meant I didn't understand the steps needed to bring this research directly to patients. To have the possibility to translate findings into treatment for patients, I had to realize that we couldn’t do it on our own, that we didn't have the funds and didn't have the drug development expertise to move forward.”

Based on a chance meeting, and a belief in this yet-to-be-proven 12/15-LOX hypothesis, Klaus was recruited in 2002 by Dr. Eng Lo who heads neuroprotection research at MGH.

“At that time I knew I had a lot to learn about stroke,” Klaus said. “We diligently worked with the researchers at MGH who specialize in animal stroke models, and they helped us to identify that 12/15-LOX is increased during an acute ischemic stroke and mediates neuronal cell death. Soon after this discovery, we were also able to demonstrate that 12/15-LOX regulates vascular damage caused by stroke.“

Between 2004 and 2006 they published on Baicalein and 12/15-LOX in the ischemic brain, demonstrating that inhibition of 12/15-LOX is protective in ischemic stroke models. This study solidified future grant funding by the NIH. Unfortunately, funding for stroke research was under duress. Due to the failure of a large late-stage Ph3 neuroprotective agent trial, many pharma companies dismantled stroke research, turning their attention to Alzheimer’s. There were few industry-sponsored research opportunities for stroke. Nonetheless, their results were too promising to ignore.

Klaus explains, “The failure of the stroke trial was around the time when we were making major scientific advancements. While certainly frustrating, we diligently remained focused on the mechanistic side to demonstrate the promise of the compound.” Stroke is an area of high unmet need, and even though it was difficult, they hoped industry would come back their way.

Currently, the standard of care for stroke is tissue Plasminogen Activator (tPA), which was approved by the FDA for ischemic stroke in 1996. The biggest drawback of tPA is intracranial bleeding. Bleeding risk significantly limits the treatment window of the drug to 3-4 hours within the onset of stroke, and it also limits the utilization of tPA to only patients with ischemic stroke. Advanced imaging in a hospital setting is often required to identify the cause of stroke before tPA administration. Due to the bleeding risk, the real-world utilization of tPA is extremely low – only ~3%-5% of stroke patients receive therapy.

Klaus and his team strove to make a drug safer than tPA and are on their way to achieving just that. He clarified, “We tested the 12/15-LOX inhibitor in mouse models of hemorrhagic stroke, and there’s no increased bleeding. Further, we found that we could reduce bleeding in the brains of warfarin-treated mice when they were given an ischemic stroke, a finding that could be important for patients with atrial fibrillation who experience a stroke”. The team envisioned without the bleeding risk, 12/15-LOX inhibitor could be given to patients as monotherapy or adjuvant to tPA. The improved safety profile could enable much broader utilization of therapy and address the dire situation of stroke patients not receiving proper treatments.

Close collaborations with other academics helped Klaus to get through the toughest moments. “At the time we knew the first generation inhibitors we were using weren’t very specific. I got in touch with Ted Holman, a lipoxygenase enzymologist at UC Santa Cruz and he started to screen for more specific lipoxygenase inhibitors.” They wanted to make sure their inhibitors would get into cells, and also inhibit both human 12/15-LOX, as well as the murine lipoxygenase present in the animal model of stroke.

By 2011 Klaus initiated a robust drug discovery effort around 12/15-LOX inhibitors. He realized he needed additional resources and expertise. Launched in 2011, The Blueprint Grant Program from the NIH not only provides significant monetary contributions but also arranges for grant recipients to meet with industry experts to help them bridge the gap between bench and clinical translation.

“We applied once early on, but our research was too premature, so we applied to other NIH grants to cover the gaps,” said Klaus. Eventually, Klaus and his team decided they have enough research, and in vivo proof of concept results to apply successfully and were awarded the Blueprint Grant in May of 2018.

Through their grant, they have already achieved the first goal of developing new assays. The next milestone will be to generate improved hits and leads. The award is planned for five years and will hopefully lead to the development of an IND ready molecule.

An introduction to the Partners Innovation Fund was another chance meeting. Through a routine seminar at Mass General Hospital, Klaus was introduced to a PIF partner, Meredith Fisher, who quickly became very interested in Klaus’ science.

Klaus explains, “Previously I had been working with our innovation department and tech transfer office, and while they are fantastic in certain areas, there were indeed gaps in translational insights and what they could do.” Getting connected with industry and working with someone who has hands-on knowledge in translation and venture is essential. Klaus continues, “We realized we didn't know much about these topics until we needed to take the next steps. The more you talk to industry people, the more it can help to refine development. Having someone working as a liaison and providing connections has helped us immeasurably.”

As for the future, Klaus won't abandon the academic side completely. He says, “We are certainly willing to participate in future drug development, but we will also be ready to hand off at some point too. For us, the thrill is seeing our academic research work yield a result we can take forward to the next level.”

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