Inherited retinal disorders and advances in gene therapy

May 1, 2026 Dr Minal Patil and Associate Professor Andrea Vincent

Inherited retinal disorders (IRDs) comprise a heterogeneous group of diseases characterised by diverse modes of inheritance, including autosomal dominant, autosomal recessive, X-linked (recessive and dominant), mitochondrial inheritance and less common patterns, such as pseudodominance. This genetic diversity contributes to significant variability in clinical presentation, disease progression and therapeutic responsiveness.

 

Advances in genetic discovery (eg. next-generation sequencing, whole-exome and whole-genome sequencing, small molecular inversion probes) have slowly increased the diagnostic yield for IRD, with over 300 genes now associated with IRDs, permitting a genetic diagnosis in up to 80% of patients¹. Simultaneously, evolution of tools to assess retinal function and ophthalmic imaging techniques (eg. full-field stimulus threshold, microperimetry, fundus autofluorescence and high-resolution OCT), along with meaningful outcome measures (multi-luminance mobility test, even with a virtual-reality headset), have set the scene for better knowledge of the underlying pathogenesis and natural history of IRDs, a prerequisite for targeted therapies and their success².

 

The integration of clinical and molecular data has paved the way for gene-targeted therapeutics, marking a paradigm shift in the management of IRDs. The development of such therapies depends on multiple disease- and gene-related factors. Disease-related considerations include the global burden of IRDs, degree of visual morbidity, age at presentation, disease stage and rate of progression. Gene-related factors include inheritance pattern, the functional impact of the mutation (eg. loss of function, dominant-negative effects) and practical considerations such as gene size, which influences vector-delivery strategies³ (Fig 1).

 

 

Fig 1. Routes of administration of viral and non-viral vectors in gene therapy³

 

 

A major milestone in this field was the approval of voretigene neparvovec (Luxturna), the first in vivo gene therapy approved by the US Food and Drug Administration (FDA) for retinal disease. This adeno-associated virus (AAV2)-based therapy targets biallelic mutations in the RPE65 gene and is indicated for patients with viable retinal cells. Delivered via subretinal injection, the therapy enables retinal pigment epithelial cells to produce the enzyme required for the visual cycle. Long-term studies (up to 15 years) have demonstrated sustained improvements in functional vision, including enhanced light sensitivity and navigation ability⁴. However, the surgical delivery carries potential risks such as endophthalmitis, retinal detachment, retinal haemorrhage, increased intraocular pressure and structural complications including foveal thinning⁵.

 

Following this breakthrough, there has been a rapid expansion in gene therapy development for IRDs. Gene-replacement strategies are currently being trialled for multiple IRD genes, including PDE6B, RPGR and RLBP1. Recent studies in AIPL1-associated retinal dystrophy have also shown promising outcomes, with improved visual acuity and evidence of slowed disease progression after subretinal delivery of AAV-mediated therapy, without significant adverse effects⁶.

 

Major limitations of gene-replacement therapy include the development of an immune reaction to the viral vector, though this can be well managed, and the inability to transfer larger replacement genes. Alternative approaches are being developed to address these limitations.

 

Gene editing and RNA-based therapies, including CRISPR-Cas systems and antisense oligonucleotides, are particularly relevant for large genes that exceed the packaging capacity of AAV vectors. For example, these approaches are being explored in CEP290-associated Leber congenital amaurosis (LCA10)⁷ (Fig 2).

 

 

 

Fig 2. AAV vectors can be used to deliver cDNA encoding replacement genes in diseases caused by monogenic recessive mutations, such as the mutation in the CEP290 gene (represented by a red cross). This vector is limited to a 4.5kB carrying capacity, which has made it suitable for gene-replacement therapy in some forms of retinal degeneration (top). A gene-editing approach with AAV carrying saCAs9 and its gRNAs for treating splice mutations has been developed. Alternatively, antisense oligonucleotides can target mutations on the pre-mRNA and do not require AAVs to penetrate the target cells⁸

 

 

For autosomal dominant retinal dystrophies, gene inhibition strategies are being explored. These involve suppression of the mutant allele (eg. RHO) combined with supplementation of the wild-type gene. However, current evidence remains limited and further studies are needed to establish efficacy⁷.

 

RNA-based therapies

An emerging example of an intravitreal RNA-based therapy is PYC-001 for autosomal dominant optic atrophy caused by OPA1 haploinsufficiency (Figs 3, 4). This therapy utilises a cell-penetrating peptide conjugated to a phosphorodiamidate morpholino oligomer (CPP-PMO) to enhance translation of the normal OPA1 allele, thereby restoring protein levels in retinal ganglion cells. Sundew, a phase 1a single ascending dose study, showed a good safety and tolerability profile. Myrtle, the phase 1b multiple ascending dose clinical trial, has commenced and we treated the first patient in New Zealand in early 2026.

 

Using a similar technology, PYC Therapeutics has an ongoing trial of an intravitreal injection of VP-001 for PRPF31-associated rod-cone retinal dystrophy, using RNA to downregulate the activity of another gene, CNOT3, which then boosts PRPF31 expression. The phase 1/2 trials (Platypus and Wallaby) showed mild and expected treatment-emergent adverse events, with mean improvements in low luminance visual acuity and microperimetry.

 

 

Fig 3. PYC Therapeutics’ enhanced RNA drug delivery mechanism. Credit: PYC Therapeutics

 

 

Pharmacological therapies primarily aim to reduce toxic retinoid accumulation or enhance cellular clearance, offering mutation-independent treatment strategies. For ABCA4-associated dystrophy, examples include:

 

• tinlarebant (LBS-008), an oral RBP4 antagonist that lowers toxic by-products
• gildeuretinol (ALK-001), deuterated vitamin A, which slows degeneration
• metformin, which clears lipofuscin in RPE
• emixustat hydrochloride – a visual cycle modulator/RPE65 inhibitor, which reduces toxic retinoids
• STG-001 – a non-retinoid RBP4 antagonist, which reduces retinal vitamin A
• soraprazan (remofuscin) – an oral therapy targeting lipofuscin clearance in RPE⁹.

 

Tinlarebant (Belite Bio) is being trialled in adolescents with ABCA4-associated Stargardt disease as a once-daily oral medication. The Dragon phase 3 trial showed a 36% reduction in the growth rate of atrophic lesions, compared with placebo, and stable visual acuity after 24 months. Dragon II is now underway. Additionally, this drug may be useful in geographic atrophy, with the phase 3 Phoenix clinical trial fully enrolled. Belite Bio is planning to file a new drug application with the FDA early this year.

 

 

 

Fig 4. Optos photos of the optic nerves of a patient with optic atrophy due to a pathogenic variant in the OPA1 gene, showing bitemporal disc pallor (above) and corresponding inferotemporal retinal nerve fibre layer thinning (below). This patient is eligible for the Myrtle PYC-001 trial

 

 

Alkeus Pharmaceuticals has just released its Tease-2 results for gildeuretinol in 80 patients aged 8–44 years over two years, showing a promising but not statistically significant 28% reduction in ellipsoid zone loss. The treatment was well tolerated and showed benefits in secondary endpoints, including low luminance visual acuity. However, the study was viewed as underpowered and the company has received Breakthrough Therapy and Orphan Drug Designation from the FDA.

 

Gene-agnostic treatments

Despite advances in technology and genetic knowledge, at least 20% of patients remain without a genetic diagnosis and the cost of developing gene-specific treatments for every known retinal gene would be exorbitant.

 

 

 

Fig 5. Optos photo and OCT of the fundus of a patient with advanced rod-cone retinal dystrophy and counting-fingers vision. The OCT shows loss of photoreceptors, but preservation of the inner retinal layers, including the retinal nerve fibre layer, which is the target for KIO-301 optogenetic therapy

 

 

Therefore, gene-agnostic treatments target the underlying pathological process, regardless of the responsible genetic defect. SparingVision has developed SPVN-006, a subretinal injection that counteracts the degeneration of cone photoreceptors by restoring rod-derived cone viability factor (RdCVF), a potent antioxidant that protects cones against oxidative stress¹⁰. The DNA of the two distinct isoforms of the NXNL1 gene is supplied via an AAV. A study is currently in phase 1/2.

 

For patients with advanced-stage disease whose photoreceptors are no longer viable, but who still have functioning inner retinal cells (Fig 5), optogenetic therapy represents a mutation-independent strategy. This approach involves introducing light-sensitive proteins (opsins) into surviving retinal cells, such as ganglion or bipolar cells, thereby restoring light responsiveness (Fig 6). Early clinical trials have demonstrated the potential for partial restoration of light perception and basic visual function¹¹. They have also shown some significant functional outcomes in cases of advanced retinitis pigmentosa. We are also commencing a clinical trial (Abacus-2) with KIO-301 (Kiora Pharmaceuticals) in Auckland in the next few months.

 

Fig 6. Illustration of optogenetic therapy with KIO 301. When exposed to light, KIO-301 flips into its ‘on’ position. This disrupts the flow of ions, which activates RGCs to process and relay light signals to the visual cortex

 

 

Overall, gene therapy for retinal disorders is rapidly evolving, with numerous clinical trials demonstrating encouraging early results. Despite ongoing challenges – such as delivery limitations, long-term safety and cost – continued advances in molecular technologies and therapeutic design are expected to significantly expand treatment options and improve outcomes for patients with IRDs.

 

References

1. Mustafi D, Hisama FM, Huey J, et al (2022). The current state of genetic testing platforms for inherited retinal diseases. Ophthalmology. Retina, 6, 702–710.
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4. Maguire AM, Russell S, Wellman J, et al (2019). Efficacy, safety, and durability of voretigene neparvovec-rzyl in RPE65 mutation-associated inherited retinal dystrophy: results of phase 1 and 3 trials. Ophthalmology,126, 1273-1285,
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8. McClements ME, Elsayed MEAA, Major L, et al (2024). Gene therapies in clinical development to treat retinal disorders. Molecular Diagnosis & Therapy, 28, 575–591.
9. Zaydon YA, Tsang S H (2024). The ABCs of Stargardt disease: the latest advances in precision medicine. Cell & Bioscience, 14(1), 98.
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11. John MC, Quinn J, Hu ML, et al (2022). Gene-agnostic therapeutic approaches for inherited retinal degenerations. Frontiers in Molecular Neuroscience, 15, 1068185.

 

 

Dr Minal Patil is an ocular genetics and paediatric ophthalmology Fellow at the University of Auckland under the supervision of A/Prof Andrea Vincent and Dr Sarah Hull. Her current research focuses on the diagnosis and genotypic evaluation of IRDs in both paediatric and adult populations. Her recent work, published in Ophthalmic Genetics, characterises novel genetic mutations in IRD in Pacific Island populations. 

 

 

Associate Professor Andrea Vincent is a clinician-scientist at the University of Auckland, practising at Greenlane Eye Department and at Retina Specialists. She established and leads the Eye Genetic team, and is the principal investigator for the Myrtle OPA1 trial and the Abacus-2 Optogenetic trial in New Zealand.