In this episode of Evidence-Based Retina, Rishi Singh, MD talks with George Magrath, MD, MBA, MS, about OPGx-LCA5 and OPGx-BEST1, Opus Genetics' gene therapies for LCA5- and BEST1-associated inherited retinal diseases (IRDs). Dr. Magrath is the CEO of Opus Genetics.
Opus Genetics gene therapy fast facts:
- Genetic testing: Dr. Magrath cites a gap between an estimated 8,000 US Best disease patients in genetic databases and a clinically recognized population closer to 24,000, based on an Opus Genetics survey of 40 retina specialists.
- LCA5: Dr. Magrath reports improvement across full-field stimulus threshold (FST) testing, BCVA, virtual-reality maze testing, and microperimetry in all 6 participants (3 pediatric and 3 adult) treated to date.
- BEST1: The gene-augmentation strategy is intended to restore bestrophin-1 (BEST1) channel function (a calcium-activated chloride channel) in the RPE to improve fluid and material handling in the subretinal space.
- Patient selection: Dr. Magrath describes Best disease progression using Gass staging, with relative stability through stage 3 followed by more rapid vision loss—variability that complicates identifying which patients benefit most.
- Pivotal LCA5 design: The eight-participant OPGx-LCA5 study uses a 6-month pretreatment period, so each participant serves as their own natural-history control, with microperimetry across the central 16 loci as a key measure.
- Subretinal delivery: Opus Genetics uses computer algorithms and surgical video analysis to quantify bleb volume, reflux and the amount of the intended dose that reaches the subretinal space.
Gene augmentation
Dr. Magrath describes Opus Genetics’ IRD programs as centered on gene augmentation, particularly in diseases with a structure-function dissociation, where retinal structure remains intact while function is lost. The portfolio includes seven gene therapy assets, including work from Dr. Eric Pierce and from Dr. Jean Bennett's lab at the University of Pennsylvania.
“We are focused particularly on gene augmentation diseases where we can restore benefit through a subretinal delivery.”
Genetic testing and patient identification
Genetic testing can complicate patient identification in IRDs, delaying care. Best vitelliform macular dystrophy illustrates this: clinicians without ready access to genetic testing often diagnose the disease without it. Genetic databases suggest approximately 8,000 US patients, but an Opus Genetics survey of 40 retina specialists puts the population closer to 24,000. Dr. Magrath ties this to Opus Genetics’ roots with the Foundation Fighting Blindness, a co-founder of the company.
OPGx-LCA5 program
Dr. Magrath describes LCA5 as an ultra-rare disease affecting an estimated 200 US children, caused by recessive loss of lebercilin, a structural ciliary protein that keeps photoreceptors elongated.1 Without it, photoreceptors "accordion down on themselves," he says. Gene augmentation aims to restore normal function.
At the time of the interview, three pediatric and three adult participants had been treated, all of whom showed improvement across every measure. Full-field stimulus threshold (FST) testing was especially notable, with retinal sensitivity improving by about 1.5 log units at both blue and red wavelengths, alongside gains in best-corrected visual acuity (BCVA), the virtual-reality maze test, and microperimetry.
Microperimetry anchors the pivotal design: the earlier study showed an average improvement of approximately 10.5 dB across the central 16 test loci. The current pivotal study has enrolled eight participants, each serving as their own natural-history control over a 6-month pretreatment period.
OPGx-BEST1 program
Opus Genetics’ BEST1 program shares LCA5's gene-augmentation concept but targets a different retinal cell type and mechanism of action. Bestrophin-1 is a calcium-activated chloride channel in the RPE that generates the electrical gradient measured clinically by electrooculography (EOG), reported as the Arden ratio.
Loss of channel function disrupts that gradient and causes a buildup of visual-cycle waste products called vitelliform material. The therapeutic goal is to restore bestrophin-1 function in the RPE's apical membrane, improving vitelliform material trafficking from the subretinal space and thereby improving visual function.
Treatment timing
Dr. Singh identifies patient selection as a particular challenge in Best disease. Some patients stay stable for long periods, while others progress more aggressively, making it hard to predict who is approaching advanced disease.
Dr. Magrath contrasts this with the faster decline typical of vasogenic retinal fluid from choroidal neovascularization, diabetic disease, or vascular occlusions. Best disease patients can keep good vision despite prominent vitelliform lesions and separation between the retina and RPE.
Using Gass staging, Dr. Magrath describes stability through stage 3, followed by substantial loss with vitelliruptive change, central scotoma and atrophy.2 Italian studies support treating before advanced vitelliruptive change.3,4
“I do think the biggest benefits will be in these earlier patients.”
Predicting that treatment window remains difficult. Dr. Magrath says Opus Genetics is exploring imaging and computer-vision approaches to identify disease progression before a patient reaches a more advanced stage.
That longer-term goal differs from the current first-in-human study, whose patients are later in the disease course, stages 4 and 5, though Dr. Magrath believes earlier treatment may ultimately bring greater benefit.
Subretinal delivery in gene therapies
Dr. Singh notes that vitreoretinal surgeons have grown increasingly familiar with subretinal delivery through retinal gene therapy studies. Dr. Magrath describes using computer algorithms to analyze surgical video and quantify how much of the intended 300-µL injection reaches the subretinal space, the extent of the resulting bleb and how much reflux occurs.
The aim is to use those measurements to refine the procedure, minimizing reflux and maximizing effective subretinal delivery.
“I don't think there's anywhere else in medicine where you're able to deliver a gene therapy like that precisely.”
Dr. Magrath also emphasizes the precision of ocular gene delivery, describing dosing in relation to the number of target RPE cells and vectors delivered.
Regulatory pathway
The small LCA5 population raises the question of what a pivotal trial and meaningful endpoint look like for such a limited patient population. The FDA introduced the Rare Disease Evidence Principles process in September 2025, providing a more flexible evidence framework for ultra-rare, genetically driven diseases.5
Through that process, Dr. Magrath describes an eight-participant pivotal LCA5 study in which each participant serves as their own control, followed for 6 months before treatment so outcomes can be compared with their pretreatment course, the current phase 3 design.6
Dr. Magrath describes ongoing work correlating structural change on OCT with retinal sensitivity at the same microperimetry location, an approach he says the FDA seems receptive to.
Key takeaways:
- All six LCA5 participants treated to date showed improvement across every measure evaluated, with FST results notable enough to move the program into a pivotal trial after just six patients.
- BEST1 gene augmentation targets a different mechanism than LCA5: restoring bestrophin-1's chloride-channel function to help clear vitelliform material from the subretinal space.
- Best disease's variable progression makes patient selection difficult; Dr. Magrath believes the biggest benefit may ultimately come from patients earlier in the disease course than those in the current first-in-human study.
- Incomplete genetic testing may contribute to a gap between genetically identified and clinically recognized IRD populations, complicating patient identification.
- Opus Genetics is using computer algorithms to analyze surgical video and quantify subretinal delivery precision.
This article was written by Sonia Kelley, OD, MS, based on the recorded video from Drs. Singh and Magrath.
