A sweet spot between academia and industry

Bence György has few regrets about leaving Boston’s big and busy academic world for the tranquility of Basel and the modest size of the Institute of Molecular and Clinical Ophthalmology Basel, which is located in a former Ciba-Geigy research building in an industrial city quarter on the banks of the river Rhine. In fact, this is exactly what György was after. Equipped with a degree in medicine and molecular genetics from the Semmelweis University in Budapest, and post-doctoral stints at Harvard Medical School and the Massachusetts General Hospital, he was more than familiar with the world of academia, both its possibilities and its limits.

Bence György.

What he wanted was a place where he could leverage his expertise in gene therapy and work on research projects that could potentially be translated into therapies. He was looking for neither an ivory tower career in academia nor the frenzy of a biotech start-up, avenues he could have easily pursued in Boston. “In the United States, the translation of technologies to therapies often occurs in small companies that lack economic freedom and rush experiments to satisfy investors,” György said, when I met him at the IOB in late spring in 2024. “Academia, on the other hand, which is focused on basic principles and is under constant grant and publication pressures, is ill-suited for large, goal-oriented projects that exceed traditional academic scopes and budgets. I was looking for a third way.” When Director Botond Roska asked him to join the IOB, the new route opened clearly before his eyes. “When I discussed my plans with Botond in Basel, he confirmed that the IOB, which offers academic freedom and is equipped for structured, goal-oriented translational programs, would be an ideal place,” György said.

The right model The first research project on which György embarked at the IOB was focused on optogenetics. It was a field in which Roska had made major inroads a decade earlier when he found that patients suffering from retinitis pigmentosa, a hereditary eye disease that affects the light-sensing retina and leads to blindness, could benefit from a gene therapy intervention – findings he had published in a paper in Science. Roska’s research showed that by genetically altering cone photoreceptor cells to produce light-sensitive proteins he could restore vision in mice. While the results showed great promise in the early research phase, it was György’s task to develop a therapy that would work in humans. But he would soon find that the early research obtained in mice results would lead to a dead end. What worked in mouse models, on which the initial research was based, did not work in humans. “The same constructs that worked very well in the mouse did not work at all in the human retina. In the first year, it was almost shocking because we didn’t get a single cell expressing what we wanted them to express,” György recalled. While the mouse model served as a successful proof-of-concept demonstrating the potential of the approach in treating blindness, a series of other questions remained unanswered and required creative solutions. First, it was unclear how to adapt the therapy for the human retina. Second, it was uncertain whether all blind patients could benefit from this therapy or if it would be suitable only for specific patient populations. Optimization, optimization, optimization In a first step, György started to work with human retina models as well as with retina organoids, retina-like structures that are produced through induced pluripotent stem cell technology from human skin cells – a technology the IOB was among the first to master in large scale. This strategic pivot was decisive to move on with the project. But the task at hand was far from easy as György and his team had to redo most of the processes outlined in Roska’s original research paper from 2010, but now focusing on human systems. Regarding the therapy, the team had to develop the entire process from scratch. This included testing gene regulatory elements such as the promoter, the control switch that turns on the activity of a specific gene, or the capsid, which refers to the protein shell of a virus that is used to deliver therapeutic genes into human cells. It was both a complex and exhausting effort, which György summed up as “optimization, optimization, optimization” to develop a potential therapy. “You can imagine how much iterative optimization there was until we got to a construct that worked robustly – and when I say robustly, I don’t mean for an academic publication, but for a clinical therapy.” A big breakthrough came when György and his team not only replicated Roska’s original proof-of-concept in human retinas and in retinal organoids but also devised a novel method that allowed the functional assessment of optogenetic tools in human retinal explants. For this, they developed a bespoke, electrode-array system that would be able to recognize whether the optogenetic gene therapy had reactivated the electrical activity of human retina. “We were able to establish a functional readout by recording from the ganglion cells,” György explained. In a nutshell, when the team stimulated the human retina with light, the ganglion cells, which are the bridging neurons that connect the retinal input to the visual processing centers, showed activation, much like they would do in a normal eye. “This, for us, was the breakthrough.” Clinic expertise But this was not the end. To make the therapy as efficient as possible, György also decided early on to start with patient stratification, adding Lucas Janeschitz-Kriegl, an ophthalmologist and Ph.D. student, to the team, who joined from the Eye Clinic of the University Hospital Basel to help them find out which patients would benefit most from the therapy. For this, the team gathered eye scans and functional data from blind patients around the world, including centers such as Budapest, Miami, and London, making it one of the largest cross-sectional studies in the world. The team, Janeschitz-Kriegl said, used artificial intelligence to analyze the data and determine the number of targetable cones in the retina. The retina consists of two types of photoreceptors: rods and cones. The rods are responsible for vision in low-light level conditions, while cones are being used for high-resolution color vision. The light-sensitive part of these photoreceptors is the so-called outer segment, a part of the cells, which functions like an antenna. The outer segment contains the critical proteins to detect light. In inherited retinal disease as well as in age-related macular degeneration, rod photoreceptors degenerate. As a result, in certain patients, cone photoreceptors lose their outer segments, but the cone cell bodies do not degenerate. In other words, cones become “dormant.” How frequently these dormant cones are present in blind patients has been completely unknown, but this is of critical importance when it comes to vision restoration therapies targeting these cells. “As the therapy aims to restore vision in these dormant cone photoreceptors by delivering a light-sensing protein using a viral vector, we wanted to find the patients who possess targetable cones,” Janeschitz-Kriegl said. “To our surprise, it was found that two-thirds of blind patients still retained dormant, non-functional cone photoreceptors.”

Lucas Janeschitz-Kriegl.

This meant that the therapy would be helpful to a potentially large number of patients suffering from inherited retinal disease as well as age-related macular degeneration, increasing the chances for its potential successful application in the clinic. This finding is crucial, as it may help the team avoid the pitfalls of other ophthalmic trials where strong proof-of-concepts failed to translate into meaningful patient outcomes. In those cases, the disease biology and the specific aspects of the disease that the therapy impacts were not studied in parallel, Janeschitz-Kriegl said. For György, the clinical study was yet another key differentiator for the work conducted at the IOB and another sign that his decision to join the institute in Basel to make an impact in translational science was the right choice as the collaboration with the clinic made a big difference. Thinking big Thanks to the IOB’s collaborative and skill-divers set-up, György and his colleagues traversed a big field and uncovered many firsts: They were the first to develop a vision restoration therapy directly in human systems and they were the first to determine the fraction of blind patients with targetable cone photoreceptor cells. “We had the ability to investigate this therapy from every angle,” György said. “This is also because we put a lot of focus on teamwork. So, instead of being fragmented to independent projects, which is typical academia, we focused strongly on collaboration between the various expert fields and especially between the clinic and the lab,” he said.

For Janeschitz-Kriegl this teamwork is likely to create palpable results in future. “Although ophthalmology has made great inroads in terms of diagnostics and the understanding of the eye, we still lack major breakthroughs for many eye diseases. Sometimes, as a clinician, you can’t offer much to patients.” The collaborative approach could change this. “The IOB can make further progress because clinicians understand patient needs and our researchers have the insight to work on innovative gene therapies,” Janeschitz-Kriegl said. “Once the human trials can start, it could bring a benefit to many patients.” The early breakthroughs bode well for the entire field, which is in dire need of new medicines. Worldwide, more than 2 billion people are suffering from some sort of vision impairment. The number of blind people is estimated to stand at around 43 million people, and this is forecast to increase to 61 million by 2050. Among other areas, the IOB, under the leadership of György, is working on a gene therapy project focused on Stargardt disease, a rare genetic eye disease that occurs when fatty material builds up on the macula. Since the disease is caused by a single faulty gene, György and his team are working on a base-editing approach that could correct the mutant gene sequence in question. Currently, Janeschitz-Kriegl explained, doctors, for example, try to treat Stargardt disease by reducing vitamin A influx to the eye. “The IOB and Bence, together with his team, are working on a gene therapy to correct the faulty genetic code. This would be a welcome alternative and it would be the most optimal solution,” he said. Six years down the road at the IOB, Bence György is far from exhausted, and he doesn’t long to go back to Boston’s academic circles or join a biotech. The IOB, for him, is a sweet stop that brings the best of two worlds together and could help potentially millions of patients receive new treatment options. “The main aim of the IOB is to solve problems, whether it be understanding why a disease is being caused or developing a therapy for it,” György said. “For this, we need brilliant people and to give them a big goal. That is what sets IOB apart and what is set to drive its future trajectory.”