Part 1: CGTs in ophthalmology: The physician and patient view
Featuring:
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Vishal Singal, Partner, Head of Patient Solutions, Beghou (host)
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Marianna Weener, Retinal Physician Scientist, Broad Institute of MIT and Harvard
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Lulian Kim, patient with retinitis pigmentosa and Translator
Read the summarized text version
A shared mutation across thousands of patients
Marianna opened by explaining how whole-exome sequencing of retinitis pigmentosa patients revealed two recurring mutations in the EYS gene. Both trace back to founders living in northwestern and southeastern Russia thousands of years ago. Because many patients carry the same mutation, a single gene-editing tool could treat the majority of them. As Marianna put it: "that changes everything."
Why prime editing is the most viable path forward
The EYS gene is too large for AAV delivery, producing a protein of 3,100 amino acids. Marianna's view is that prime editing is currently the most viable path. Unlike earlier CRISPR approaches that break both DNA strands and risk triggering cell death, prime editing works on one strand. Timing matters: treating patients while the outer nuclear layer and ellipsoid zone are still preserved gives the best chance of halting deterioration. On safety, Marianna noted that current data shows gene editing in the eye stays within ocular tissue, making it comparatively safer than systemic approaches for muscular or neurological disease.
What patients need from treatment
Lulian navigates at home from memory, but the moment she steps outside, simple things become challenges. She is not asking for a miracle. Her ask is that the deterioration stops. Preserving what remains, she said, is already something incredibly valuable.
The gap between regulatory criteria and clinical reality
That raised a real tension. Marianna noted that regulators often require measurable improvement in vision to approve a therapy, whereas for patients like Lulian, stabilization is already a significant milestone. This debate is ongoing and not unique to retinal disease.
Part 2: CGTs in ophthalmology: The outlook for gene therapy in the ophthalmology space
Featuring:
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Vishal Singal, Partner, Head of Patient Solutions, Beghou (host)
-
Marianna Weener, Retinal Physician Scientist, Broad Institute of MIT and Harvard
Read the summarized text version
Why Luxturna remains the only approval nine years on
Nine years after Luxturna was approved as the first gene therapy in ophthalmology, there is no second Luxturna. Marianna explained why the eye was the right place to start: small doses (around two micrograms), accessible anatomy, and the ability to measure outcomes at a cellular level before and after treatment. Luxterna showed both safety and efficacy in children with severe inherited blindness and delivered a real, observable change in their ability to navigate in low light.
Endpoints that do not fit the disease
The difficulty since then is that many conditions in the pipeline do not produce dramatic measurable change within the timeframes regulators expect. For Usher syndrome, where vision deteriorates slowly, the difference between treated and untreated patients over three years can be too subtle to meet current approval criteria, even when the therapy is safe. Marianna's point is that endpoints need to differ by specialty, and ophthalmology is not oncology.
The four groups whose coordination the field depends on
On the broader ecosystem, Marianna identified four groups whose coordination matters: patients and their advocacy organizations, physicians who observe disease progression over years or decades, researchers developing treatments, and the business and legal infrastructure. She was direct that patient advocacy groups have become practically a prerequisite for starting treatment development, and that in the US, EU, and Japan, this is already advancing, but many voices globally remain unheard.
Where investment is going and where it should
Marianna also flagged what she called the herd paradox: multiple companies concentrating on one safe, familiar target while broader unmet need goes unaddressed. Her alternative is a blue ocean approach, as there are enough viable targets to develop, each with endpoints appropriate to that field. She also raised genomic data privacy as a practical tension: treatment requires knowing a patient's mutation, but sharing that information carries real legal and ethical risk that the field has not fully resolved.
The gap between science and infrastructure
Vishal's observation was that the science is moving faster than the infrastructure around it. Regulation, legal frameworks, and patient communities are not keeping pace, and that gap is where the work is.
Key takeaways:
- So-called “founder-effect” variants change the development calculus: When many patients share the same mutation, it becomes the foundation for treatment, because one editing tool can treat the majority.
- One example of this shared ancestry is the EYS gene mutation which affects up to 20% of retinitis pigmentosa (RP) patients in Russia and 30% in Japan.
- Gene editing, rather than gene replacement, is the most credible current tool for treating EYS mutations, because an AAV (Adeno-associated virus) cannot deliver this construct. Safer forms of gene editing, like prime and base editing, avoid the double-strand DNA breaks that risk triggering cell death.
- In the opinion of retinal specialists and patients with RP, regulatory endpoints for this disease need to move away from requiring measurable vision improvement. Stabilization is a meaningful outcome for patients and needs to be recognized as such by regulators, they argue.
- Nine years on, there hasn’t been another Luxturna, the gene therapy approved for hereditary blindness. The bottleneck is not biology. Rather, approval frameworks, genomic data governance, and patient infrastructure are not keeping pace with the science.
- In addition, investment in gene therapy tends to concentrate around familiar targets, as is the case in many areas of drug development. The ophthalmology field has enough viable targets and enough tools for biotech to take a broader view, with endpoints calibrated to this specialty rather than borrowed from oncology.