Mit welchen Herausforderungen die Entwickler neuer Gentherapien in der Augenheilkunde konfrontiert sind, erklärt Experte Prof. Dr. Bart Leroy von der Uniklinik Gent. Der Keynot-Redner der DOG 2025 war als Arzt vor vielen Jahren an der Zulassung von Luxturna beteiligt. Heute vermittelt er als Aufklärer und Lobbyist zwischen Pharmaindustrie und Zulassungsbehörden.
Concept Ophthalmology: In your keynote at the DOG Congress, you highlighted the challenges faced by developers of gene therapies. The field is booming, despite major financial and regulatory hurdles. What are these hurdles—and how do they affect progress?
Prof. Dr. Bart Leroy: Thanks to anti-VEGF medications, we have seen spectacular successes with AMD and DME patients since the 2000s. When it comes to approving new drugs, regulators are used to seeing visual improvements of 10 or 15 letters on a reading chart. New therapies are measured against this standard. Such results are attractive to pharmaceutical companies and regulatory authorities because they are clear and easily demonstrable.
However, the situation is completely different for genetic therapies targeting inherited retinal disorders (IRD): Patient numbers are much lower, the expected market is less profitable for the industry, and disease courses are more diverse and less clear-cut. Measurable treatment success is harder to define, as improvements are often subtler or occur after a longer period. Standardized measurement methods fit to show improvement of functional vision often do not exist, so new ones must be established and certified first.
Additionally, IRD patients typically start with a much lower retinal quality than those with common eye diseases who lose vision later in life. Many IRD patients have never had a normally developed retina or normal neurovisual development. Hence, their starting conditions are worse, and the possible range of improvement is more modest. Yet even the smallest gain makes a huge difference in quality of life for those affected. Our challenge is how to communicate to regulators that this improved visual function benefits functional vision for patients and therefore is to be considered meaningful.
How could the evaluation criteria for IRD therapies be adapted?
I advocate for different success markers for IRD therapies—such as those measuring stabilisation or slowing of disease progression, as is recognised e.g. in oncology. In cancer medicine, a life extension of six months is considered a success and leads to therapy approvals.
When I ask my patients, “Would you be satisfied if we could maintain your current vision?”—most answer, “Yes, absolutely!” If we continue to apply the same standards as for common diseases, we face an ethical dilemma.
Can you give an example of how a gene therapy works and the effect it has on patients?
Luxturna is a gene therapy for RPE65 gene defects, used mainly in children and adults who still have enough target cells. No new cells are generated; instead, the function of existing cells is optimised.
Who needs this therapy and why?
Patients who inherit a defective RPE65 gene from both parents lack the key protein for vitamin A recycling in the visual cycle. As a result, they are practically blind—except in very bright light.
During therapy, a functional copy of the gene is packaged into a virus, which is injected directly under the retina in billions of copies. This “gene taxi” delivers a working gene copy into the cells, allowing the crucial protein to be produced again. While the therapy has little effect on best-corrected visual acuity, retinal light sensitivity improves dramatically: patients who previously saw nothing except in very bright conditions, can perceive things in much darker environments.
What kind of vision do these patients have?
Before therapy, even in sunlight, patients see only silhouettes of people and things. After therapy, they can recognize whether a person is male or female, old or young, even in dim light. The gain in perception is immense and often appears within two weeks, reaching its maximum after six months.
For example, the boy who became the first patient worldwide to be treated with Luxturna twenty years ago was able to see the night lights of a city from an airplane just two weeks after treatment—in his treated eye. Although his visual acuity was not restored, his light sensitivity and visual field improved so much that he now leads an independent life as an adult and was able to complete his studies aided by his vision—previously unthinkable.
What methods are used to measure improvements in visual quality?
We developed a new endpoint for studies: the Multi Luminance Mobility Test. Participants complete an obstacle course under seven different light levels. After therapy, all patients could complete the course even in semi-darkness, which was previously impossible for them. The FDA and EMA have recognised this method as an acceptable endpoint. However, we need more ways to measure the nuances of low vision in a standardised way, and not all innovative measures are accepted by regulators. If we achieve only minor improvements or preserve quality of life a bit longer, the FDA and EMA say, “Not good enough.” This makes it unattractive for pharma companies to invest in this type of research, and many withdraw, causing urgently needed research funding to dry up. Moreover, many inherited retinal diseases progress slowly, so it takes a long time to prove a therapy’s benefit. Investors don’t want to wait 20 years; they want relatively quick returns.
So, since Luxturna’s approval, there have been no new gene therapies for IRDs?
Correct. Since Luxturna’s FDA approval in 2017 and EMA approval in 2018, ophthalmology has been waiting for further gene therapies, mainly due to regulatory hurdles.
How did you become a researcher, networker, and advocate in the field of gene therapy?
Medicine is a calling for me, and I want to do everything possible to bring promising drugs to patients. During my medical studies in Ghent, I was interested in both ophthalmology and genetics, so I studied both. My goal was to specialize in inherited retinal diseases, which led me to Moorfields Eye Hospital in London, where I learned from Professor Alan Bird—a pioneer in the field. There I built international contacts and friendships that form my network to this day. I work as a clinician in the field of ocular genetics, which also includes elaborate functional diagnostics. As a clinician, I founded an ophthalmic genetics department in Ghent in 2001 and became head oft the Ophthalmology Department in 2016.
I am not only a researcher and clinician but also an advocate, negotiator, and networker after seeing a drug fail in a regulatory study in 2022. The failure was mainly due to the study design. We had developed a short RNA molecule that docked onto pre-mRNA like Velcro and corrected its maturation into functional RNA. The drug showed positive effects, but they weren’t sufficient for the FDA’s requirements, mainly due to what is, in my view, a failed study design, that FDA had demanded.
As a result, the company—a small biotech startup—gave up, and the product disappeared. The entire research and development effort was lost. I thought this was uancceptable and started some advocacy work. We succeeded in bringing together regulators, pharma industry, IRD specialists worldwide, and patient organizations for the first time. We call these meetings “multi-stakeholder meetings”—now held regularly, organised into a project called Act4RED (RED = rare eye diseases).
The product that started my crusade now belongs to Théa Pharma and is getting a second chance under the name Sepul Bio. The clinical trials have just begun and will hopefully bear fruit.
Can you give another example from your work?
We are also negotiating the approval of a drug developed by Johnson & Johnson (J&J) with London startup Meira GTX. It’s a therapy for X-linked retinitis pigmentosa, a severe retinal disease mainly affecting men, since they have only one X chromosome. Women with a defective X are genetically more protected, as they have a second healthy X, which can even be seen in specialized retinal imaging.
What was the obstacle for this gene therapy?
J&J started a Phase 3 study in which we treated seven patients. The primary endpoint was a navigation course, similar to the Multi-Luminance Mobility Test. This was may be not such a good choice, as men with advanced rod-cone dystrophy have such restricted visual fields that navigation improvement is hardly possible. As a result, the primary endpoint was missed, even though many secondary measurements were positive. J&J stopped the project. We are now trying to convince the company not to give up and to discuss these positive secondary endpoints with regulators. But J&J is faced with the reality that the trial showed no significant improvements with the primary outcome measure.
Couldn’t the study be repeated with a new primary endpoint?
Theoretically yes, but the company faces the risk of investing another 100 million euros and failing again. Such approval studies are extremely expensive, mainly due to legal safeguards, not necessarily the treatments themselves.
What chances do patients with ultra-rare inherited diseases have under such difficult circumstances?
For ultra-rare diseases, there are often only a few patients per country. They could all be treated in a single study, and afterwards, there would be no classic market for the drug. That’s why I propose treating affected individuals with ultrarare disease within a study. If you use public funds or research grants and reduce bureaucracy, this approach becomes feasible.
For example, certification of already proven transport platforms should be dropped to save costs. If you buy a truck for a shipping company, you don’t need to check before every trip whether it’s suitable for transporting flowers or furniture. Similarly, established gene therapy platforms should be recognized. This is only one measure of how we could pave the way for cheaper drug development.
You said in your DOG keynote that despite strong regulation and low financial support, the field of gene therapy is booming. Are we just at the beginning?
Absolutely. Even though the road ahead is long and rocky, I am confident that we will achieve our goals in the long term and make effective gene therapies accessible to our patients. In our multi-stakeholder meetings, we now speak with regulators two or three times a year, and they have begun listening and giving advice. At the FDA and EMA, a new generation of ophthalmologists—many of them women—are now working. They understand the complexity of the issue and think pragmatically and scientifically. As always, open and respectful communication is key.
Finally, a philosophical question. You say: “It is a human right to know your own genome.” How can this human right be implemented democratically and ethically?
That is a very important question. I am convinced that everyone has the right to know their own genotype—if they wish. There are many reasons for this. Knowing your genes gives you certainty. We can make healthy lifestyle decisions in time, detect as yet asympromatic hereditary diseases before they commence, intervene early, and prepare for possible consequences. Our genome provides clarity about our health outlook and has helped with family planning for over twenty years. Of course, a simple genetic test is not enough; you need accompanying analysis and expert counseling. The right to knowledge includes the right to understandable advice. In Belgium, clinical genetics already follows this standard. To implement it worldwide, we will need more specialists, such as geneticists and genetic counselors. Only then will genetic knowledge be truly useful for laypeople.
I am critical of genetic tests offered by providers who do molecular screening without expert advice given to patients afterwards. Data protection is also crucial. Only the affected person should decide who knows their genome and to whom they disclose this information. Insurers, in my view, have no right to demand genetic information, though they try repeatedly to protect their own interests. That is not fair—insurance should find business models that serve all people, not just the healthy. But that is what one observes when the interests of shareholders is diametrically opposed to the interest of your paying clients.
Bart Leroy, MD, PhD, is a certified ophthalmologist and clinical geneticist, as well as Professor of Ophthalmology, Ophthalmic Genetics, and Visual Electrophysiology at Ghent University. He heads the Department of Ophthalmology at Ghent University Hospital and is an expert in inherited retinal degenerations (IRD) such as Leber congenital amaurosis, Stargardt disease, and retinitis pigmentosa. His focus is on clinical phenotyping, genotype-phenotype correlations, and the development of new IRD therapies, especially gene therapies. Dr. Leroy has been principal investigator in several clinical trials, including gene therapies for CEP290- and RPE65-IRD, and was involved at the Children’s Hospital of Philadelphia in the development and launch of Luxturna, the first approved ocular gene therapy. He is also active in several international professional societies and working groups for genetic eye diseases, such as the European Society of Retina Specialists (Euretina), where he is board member for IRDs, and he is general secretary of the International Society for Genetic Eye Diseases and Retinoblastoma (ISGEDR).
Kontakt:
Prof. Dr. Bart Leroy
UZ Gent
C. Heymanslaan 10
9000 Gent
bart.leroy@ugent.be
Das Interview führte Rosemarie Frühauf. Es erscheint in deutscher Sprache in Concept Ophthalmologie 9-2025.
