Ivie Itua
Clinical Research Fellow, Imperial College London, London, UK

The advent of gene augmentation therapy for inherited retinal dystrophies (IRDs) marks one of the most significant therapeutic shifts in paediatric ophthalmology. The approval of voretigene neparvovec for RPE65-mediated retinal dystrophy demonstrated for the first time that genetic diseases causing childhood blindness could be treated rather than merely supported. The pivotal phase 3 trial provided robust evidence of functional visual improvement, particularly in low-luminance mobility, with sustained benefit over several years of follow-up (1–3). Real-world paediatric data further corroborated meaningful visual gains after treatment (4). These results influenced regulatory frameworks, such as the National Institute for Health and Care Excellence (NICE) HST11 guidance, which underlined the importance of sufficient viable retinal cells before gene therapy can be effective (5).

Within this accelerating therapeutic landscape, AIPL1-associated retinal dystrophy has emerged as an important and challenging model for understanding what is achievable with paediatric gene therapy. Its strikingly early onset, rapid progression, and narrow therapeutic window place exceptional demands on diagnostic, genetic, and imaging pathways. At the same time, recent first-in-human results have shown that meaningful rescue is possible in children treated early enough, making AIPL1 disease a crucial case study in the emerging era of paediatric retinal gene therapy. This educational article aims to equip ophthalmology trainees with the knowledge to:

1. Describe the clinical spectrum and natural history of AIPL1-associated retinal dystrophy and its implications for timing of gene therapy.
2. Explain the rationale for gene augmentation therapies in paediatric inherited retinal dystrophies and contrast AIPL1 with RPE65-mediated disease.
3. Summarise the first-in-human AIPL1 gene therapy trial and its implications for clinical practice.
4. Identify translational, ethical, and methodological challenges in paediatric retinal gene therapy.
5. Apply practical lessons regarding early diagnosis, imaging, referral, and family counselling.

AIPL1-Associated Retinal Dystrophy: Pathophysiology and Natural History

AIPL1 encodes a photoreceptor-specific co-chaperone essential for the assembly and stability of phosphodiesterase-6 (PDE6) within the phototransduction cascade. Loss of AIPL1 function results in severely reduced PDE6 levels, dysregulated cGMP, and rapid photoreceptor degeneration, a mechanism supported by animal models and human retinal organoid studies (6,7). Clinically, AIPL1-related disease presents within the first weeks of life with profound visual impairment, poor fixation, wandering nystagmus, and extinguished or markedly reduced electroretinographic responses (8,9). The fundus appearance in early infancy may be deceptively normal before progressing to macular atrophy, loss of outer retinal structure, and intraretinal pigment migration during later childhood.

Natural-history studies have shown that the foveal outer retina in AIPL1-associated disease is preserved only for a brief period early in life. Detailed optical coherence tomography (OCT) imaging demonstrated relatively intact foveal lamination in children younger than approximately four years, with rapid decline thereafter (10). Emerging genotype-phenotype analyses have further identified variability in disease severity, including milder early-onset severe retinal dystrophy in children with specific hypomorphic or missense variants (7,11). Nevertheless, the predominant phenotype remains one of ultra-early degeneration, making the therapeutic window narrow and dependent upon extremely early diagnosis and structural assessment.

Why AIPL1 Is a Critical Test Case for Paediatric Gene Therapy

AIPL1-associated retinal dystrophy is characterised by rapid, early photoreceptor degeneration, making it an ideal stress test for the principles governing gene-based therapies. Preclinical studies in AIPL1-deficient mice demonstrated that adeno-associated viral (AAV) gene augmentation could partially rescue photoreceptor structure and function, but only when delivered before significant degeneration had occurred (12). This evidence parallels the human natural-history findings and reinforces the principle that the timing of intervention is central to therapeutic success.

The requirement for preserved foveal architecture also positions AIPL1 as a key example of why early structural imaging is essential. In AIPL1 disease, residual foveal outer retinal layers may be extremely thin but nonetheless represent the only viable substrate for functional rescue. For clinicians and trainees, this necessitates early OCT imaging, skill in interpreting subtle features of paediatric retinal anatomy, and rapid referral pathways to IRD-specialist centres for genetic confirmation and consideration of emerging therapies.

First-in-Human AIPL1 Gene Therapy: A Landmark Study

The first-in-human AIPL1 gene therapy study, published in The Lancet in 2025, marked a major milestone in the management of severe paediatric IRDs. Michaelides and colleagues conducted an open-label, early-phase interventional study involving four children aged 1.0–2.8 years with biallelic disease-causing AIPL1 variants and preserved foveal structure identified using handheld OCT (13). Each child received a unilateral subretinal injection of an AAV8 vector expressing AIPL1 under the control of a photoreceptor-specific promoter.

The results demonstrated substantial structural and functional visual improvement in treated eyes over a mean follow-up of 3.5 years. Visual acuity improved from the light-perception range to measurable acuity around 0.9 logMAR, while untreated fellow eyes showed progressive decline. Visual evoked potentials revealed stronger cortical responses in treated eyes, and OCT imaging showed better preservation of foveal lamination compared with untreated eyes (13). The safety profile was favourable, with only one case of transient cystoid macular oedema and no persistent inflammatory or systemic complications.

These findings align with earlier reports from UK specialist centres documenting meaningful functional gains in children treated compassionately with AIPL1 gene therapy, including improved object recognition, enhanced navigation, and the ability to read large print (14,15). Together, these studies provide compelling evidence that even in the most severe early-onset IRDs, gene therapy can restore functional vision when delivered during a critical developmental window.

Clinical Lessons for Ophthalmology Trainees

The experience with AIPL1 gene therapy highlights several important lessons for clinical practice. The first is the paramount importance of timing. AIPL1 disease progresses rapidly, and the therapeutic window corresponds closely to the period during which foveal photoreceptors retain structural integrity. Children must therefore be recognised promptly, imaged early, and genetically diagnosed without delay. This underscores the need for streamlined referral pathways for infants presenting with profound visual impairment or nystagmus and for the incorporation of handheld OCT into routine paediatric ophthalmic assessment.

A second major lesson concerns the concept of retinal viability. The threshold for “sufficient viable retina” is considerably narrower in AIPL1 than in conditions such as RPE65-mediated disease, where structural preservation is more extensive and progression more gradual. Trainees must become adept at recognising very thin but laminated outer retinal layers that may represent the only substrate for rescue.

Thirdly, the methodology of paediatric outcome measurement requires adaptation. Traditional visual acuity charts and visual field assessments are often inappropriate for preverbal children. The AIPL1 interventional study incorporated developmentally appropriate touchscreen-based acuity tasks, structured play-based assessments of functional vision and objective electrophysiological measures. These techniques are likely to become increasingly important as more paediatric IRD therapies reach clinical trials.

Finally, AIPL1 disease highlights broader ethical and policy considerations in paediatric gene therapy. Parents are required to consent to irreversible interventions in very young children, often with limited long-term safety data. Treatment is typically unilateral for safety reasons, creating asymmetrical outcomes but preserving internal controls. Access to therapy may be constrained by cost, infrastructure and eligibility criteria, as illustrated in health-technology assessments of RPE65 therapies (5). These factors emphasise the need for transparent family counselling, multidisciplinary coordination and ongoing evaluation of access and equity in the delivery of genomic medicine.

Future Directions

Therapeutic innovation in AIPL1 disease is likely to continue. New AAV constructs, optimised promoters, and combined gene-and-cell approaches are under investigation. Readthrough therapies targeting specific AIPL1 nonsense variants have shown early promise in experimental systems (16). Clinical development pipelines now include additional AIPL1 gene therapy candidates such as LX107 (17), and recent industry partnerships, most notably the acquisition of AIPL1 gene therapy programmes by Eli Lilly—highlight the growing strategic importance of this field (18).

As these developments accelerate, ophthalmology trainees must cultivate familiarity with IRD genetics, advanced imaging, and emerging therapeutic platforms. AIPL1-associated retinal dystrophy provides a uniquely instructive model for the integration of basic science, translational research, and clinical care in the era of paediatric precision medicine.

Conclusion

AIPL1-associated retinal dystrophy represents both one of the most severe and one of the most instructive paediatric IRDs for understanding the evolving potential of gene therapy. Its natural history underscores the importance of timely diagnosis, early imaging, and prompt genetic testing. Evidence from the first-in-human study demonstrates that meaningful visual rescue is achievable when treatment occurs within a narrow developmental window. For trainees, the lessons of AIPL1 disease provide essential preparation for the expanding therapeutic landscape of paediatric retinal gene therapy, where early intervention, structural viability, ethical reasoningg and developmental assessment converge to shape clinical decision-making.

References

1. Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in RPE65-mediated inherited retinal dystrophy. Lancet. 2017;390:849–860.
2. Drack AV, Bennett J, Russell S, et al. Four-year outcomes after voretigene neparvovec. J AAPOS. 2019;23:226.e1–226.e5.
3. Testa F, Gallo B, Rossi S, et al. Voretigene neparvovec for inherited retinal dystrophy: clinical outcomes and open questions. Eye (Lond). 2024;38:423–433.
4. Daruich A, Rateaux M, Batté E, et al. Twelve-month outcomes after voretigene neparvovec in paediatric patients. Br J Ophthalmol. 2024;108:1130–1138.
5. National Institute for Health and Care Excellence. Voretigene neparvovec for treating inherited retinal dystrophy caused by RPE65 gene mutations (HST11). NICE; 2019.
6. Sacristan-Reviriego A, Piñeiro-Gallego T, Riera M, et al. Functional analysis of AIPL1 variants in inherited retinal dystrophy. Sci Rep. 2020;10:17294.
7. Zhang Q, Wang H, Xu Y, et al. Clinical and molecular characterisation of AIPL1-associated early-onset severe retinal dystrophy. Am J Ophthalmol. 2024;257:47–57.
8. Dharmaraj S, Leroy BP, Sohocki MM, et al. Phenotype of Leber congenital amaurosis in AIPL1 mutations. Arch Ophthalmol. 2004;122:1029–1037.
9. Pennesi ME, Weleber RG, Michaels KV, et al. Residual ERGs in AIPL1-associated Leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2011;52:816–822.
10. Aboshiha J, Dubis AM, Cowing J, et al. Preserved outer retina in AIPL1 Leber’s congenital amaurosis: implications for gene therapy. Ophthalmology. 2015;122:859–868.
11. Sacristan-Reviriego A, Piñeiro-Gallego T, Riera M, et al. Mechanisms of pathogenicity in AIPL1 variants. Sci Rep. 2020;10:17294.
12. Perdigao PRL, Takahashi VKL, Ribeiro RM, et al. Gene and cell therapy for AIPL1-associated Leber congenital amaurosis. Curr Gene Ther. 2019;19:14–24.
13. Michaelides M, van der Spuy J, Naylor S, et al. Gene therapy in children with AIPL1-associated severe retinal dystrophy: an open-label, first-in-human interventional study. Lancet. 2025;405:649–660.
14. Evelina London Children’s Hospital. Innovative eye gene therapy performed at Evelina London. 2024.
15. The Guardian. Doctors in London cure blindness in children with rare condition. Feb 2025.
16. Translational readthrough therapy for AIPL1-associated Leber congenital amaurosis type 4. bioRxiv. 2021. doi:10.1101/2021.12.17.473147.
17. ClinicalTrials.gov. LX107 gene therapy for AIPL1-associated retinal dystrophy (NCT07063030).
18. Reuters. Eli Lilly signs deal for MeiraGTx’s gene therapy for severe eye disease. Nov 2025.