Inherited Retinal Diseases: Recent Trial Results and Remaining Challenges

While genetic testing is on the rise – and showing promise for patient selection – innovative treatment options are lagging. But some breakthroughs could soon emerge

Inherited retinal diseases (IRDs) are a group of diverse conditions, including retinitis pigmentosa (RP), Leber congenital amaurosis, Bardet-Biedl syndrome (BBS), Stargardt disease (STGD), and congenital stationary night blindness, among others. Inherited retinal diseases usually leads to significant vision loss that, without intervention, can progress to blindness. IRDs can range from congenital cases to those involving the elderly. Voretigene neparvovec, an adeno-associated virus vector-based gene therapy, is the only approved treatment for these disorders.

The need for additional breakthrough treatments is clear, yet there are significant challenges in assessing therapies for these rare disorders. We summarize recent clinical trials – most published in 2024 – and ask a vitreoretinal expert to assess the IRD management landscape and discuss remaining hurdles.

The Societal Burden and Familial Impact of IRDs
The need for additional treatments was recently demonstrated in an analysis published in 2024 that uncovered the total cost of these disorders on society.  Investigators performed a systematic review of nine cost-of-illness studies for IRDs across 4 countries. Per-patient per-year costs and cost ranges reflecting both direct health care costs and overall costs to society were reported:

• United States: $33k to $186k
• United Kingdom: $22k to $37k
• Canada: $16k to $275K
• Japan: $21k
• Singapore: $7k

The authors estimated that in the US, lifetime cost is more than $3.4 million per person, with nearly 90% of that cost societal. Patients with IRDs are more likely to live in poverty, experience a lower quality of life, and have limited employment opportunities due to vision loss. Researchers urged that societal costs of IRDs be considered in future clinical trials.

The impact of IRDs on families was recently assessed in a retrospective study published in 2024 that identified common IRD alleles and the burden produced by these variants.

Investigators reviewed the records of individuals with IRDs diagnosed at a single center in the UK over a 17-year period ending in 2020. They looked for variants in the 5 most frequent genes, comprising ABCA4, USH2A, RGPR, PRPH2, and BEST1, along with common variants found in the cohort. Among the results:

• More than 4400 individuals from nearly 4000 families with molecularly diagnosed IRD were identified
• 1840 individuals from nearly 1700 families (43%) had IRD-linked variants in one of the five most common genes
• Complex alleles caused disease in 17% of families with ABCA4 retinopathy
• 43% of individuals with USH2A-related IRD carried USH2A exon 13 variants
• Among RPGR variants, 7 of 10 were grouped in the ORF15 DNA region
• PRPH2 and BEST1 variants were linked to multiple IRD phenotypes
• Five of the 20 most prevalent variants found in the cohort — CNGB3, BBS1, TIMP3, EFEMP1, and RP1 — were not observed in the five most frequent genes.

The authors said their work helps to integrate genomics into ophthalmology practice, adding that it “represents the largest molecularly diagnosed IRD cohort to date. This knowledge will provide a framework for efficient interpretation and analysis of putative disease variants that will be identified through increasingly available genetic testing for IRD patients, resulting in improvement in diagnosis and management of affected individuals and their families.”

Perceived Value of Genetic Testing
Patient experience with genetic testing was evaluated in a cross-sectional survey and published in 2024. Investigators in Australia conducted an online survey of adults with IRDs and parents/guardians of minors/dependents with IRDs (n = 135) to assess knowledge, testing outcomes, and perceived value of testing. Nearly 7 in 10 respondents reported that their decision to be tested was based on a desire to contribute to research. About two-thirds said they were seeking to have their IRD more clearly defined. Sixty-three percent said they were tested to determine clinical trial eligibility.

Eighty-five percent reported having very little or no hesitation about being tested. Most respondents discussed the results with family members. Those who did not were concerned that family members would not understand the results, would be scared by them, or would not be impacted by the results.

Researchers found that most did not regret being tested. They concluded that “genetic testing can empower patients to learn about the cause of their IRDs and their eligibility for upcoming clinical trials and approved treatments. This is particularly important in the current era of personalized genomic health and the emergence of IRD gene and cell therapies.”

Recent Success with Voretigene Neparvovec
Clinicians are largely limited to using genetic testing and low-vision rehabilitation to manage individuals with IRDs. The exception is voretigene neparvovec. Approved in 2017, it treats patients with IRDs caused by mutations in both copies of the RPE65 gene.

Results from a small single-center, retrospective, longitudinal case series published in 2024 demonstrate that the treatment is beneficial, particularly in younger eyes. Voretigene neparvovec stabilized best-corrected visual acuity (BVCA) and retinal thickness, and improved low-luminance visual acuity (LLVA), chromatic full-field stimulus threshold (FST), and scotopic and photopic 2-color threshold perimetry (2CTP).

Investigators reviewed patient records following treatment with voretigene neparvovec in 30 eyes of 19 patients (10 pediatric eyes and 20 adult eyes). Among the findings:

• Overall, BCVA did not improve or worsen. However, it worsened meaningfully in 5 adult eyes and improve meaningfully in 2 adult eyes and two pediatric eyes
• LLVA improved dramatically in pediatric eyes, but not adult eyes
• All pediatric eyes showed continuous improvement in 2CTP. Only the youngest adult eyes improved similarly
• Among eight pediatric eyes with 12-month follow-up data, five had meaningful gain of scotopic FST to blue stimulus, and three experienced such to white stimulus
• Among adult eyes, meaningful blue stimulus gains was seen in 5 of 11 eyes and white stimulus gain was observed in 5 of 15 eyes
• Development/accentuation of preexisting atrophies was seen in 13 of the 26 eyes seen at 12 months

The investigators noted that the improved LLVA in pediatric eyes underscores the need to begin treatment earlier when possible. They also recommended testing for LLVA routinely.

The impact of stem cell therapy on IRDs is being investigated as a possible treatment for RP and STGD. A recent meta-analysis assessed 21 studies that used stem cell therapy on 496 eyes — 404 with RP and 92 with STGD. In individuals with RP, BVCA improved 49% at 6 months and 30% at 12 months. Only the 6-month improvement was found to be statistically significant. For STGD, visual acuity improved at both 6 months (60%) and 12 months (55%); both were statistically significant. Suprachoroidal space injection appeared to work better in individuals with RP versus those with STGD. Researchers acknowledged that studies with larger sample sizes and multicenter randomized clinical trials with longer follow-up periods are necessary to determine long-term benefits and safety.

The Challenge of Funding Rare IRD Trials
We asked a vitreoretinal expert to weigh in on what the results of these trials portend for clinical practice. Mitul Mehta, MD, MS, FASRS, Clinical Associate Professor of Ophthalmology at the Gavin Herbert Eye Institute, University of California, Irvine, noted that most retina specialists in the US currently do not treat IRDs. Clinicians increasingly offer genetic testing, due to the widespread availability of no-cost genetic screening panels. “However,” he explained, “the problem comes with what to do with the results since there are no FDA-approved therapeutics other than voretigene neparvovec.”

He added that while clinical trials offer hope for many patients, significant hurdles exist for less common retinal dystrophies. “Most patients are referred to an academic medical center or a low vision optometrist, then a retina specialist or general ophthalmologist. Many are told nothing can be done for them.”

A Potential Trial Template
Dr Mehta, who is also Fellowship Director of Vitreoretinal Surgery at UC Irvine, explained that until funding for rare IRDs increases, progress in this area will be slow. He added that the clinical trials assessing ABBV-RGX-314 gene therapy to treat wet age-related macular degeneration are a potential template for IRD researchers to follow. A Phase 3 trial is evaluating a delivery mechanism of ABBV-RGX-314 consisting of surgery and a one-time injection. A second mechanism, involving a one-time, in-office treatment, is being assessed in a phase II study. Interim results of that trial were recently released, showing early promise of the gene therapy emerging as a new standard of care.

Thus far, it is well tolerated in tests on more than 100 patients using three dosage levels and has no drug-related serious adverse events. Moreover, in 50 patients treated at the most recently added dosing level of 1×10¹² genomic copies per eye, there was an 80% reduction in annualized treatment burden, with half the patients remaining injection-free. Currently, available anti-VEGF therapy is often not well tolerated, given the need for repeated injections, leading to undertreatment and eventual vision loss. If these results hold up during further clinical trial scrutiny, ABBV-RGX-314 could become the preferred treatment option.

Dr Mehta was quick to point out that the success being seen with ABBV-RGX-314 will be challenging to replicate for rarer IRDs. “AMD is a big target with a large population of patients who could potentially benefit from gene therapy treatment.” The rarer IRDs do not get the same amount of attention and funding.