A pioneering gene therapy trial reported in The Lancet by Prof Michel Michaelides (UCL Institute of Ophthalmology and Moorfields Eye Hospital), Dr Yannik Laich and colleagues at Moorfields Eye Hospital and Great Ormond Street Hospital for Children (London, UK), has shown life-changing visual improvements in children with Leber Congenital Amaurosis type 4 (LCA4), a rare and severe inherited retinal dystrophy caused by mutations in the AIPL1 gene.1 Infants with pathogenic variants in the AIPL1 gene experience severe and rapidly progressive vision loss starting at birth.
This non-randomised, single-arm, open-label, first-in-human interventional study included four children aged 1-3 years with congenital severe retinal dystrophy, biallelic disease-causing variants in AIPL1, and relative preservation of outer retinal structure at the central macula on OCT . The therapy involved a 60-minute keyhole procedure in which rAAV8.hRKp.AIPL1, a recombinant adeno-associated viral (AAV) vector, delivered functional copies of the AIPL1 gene directly into the subretinal space. Efficacy was evaluated through multiple outcome measures, including visual acuity, functional vision, steady-state visual evoked potentials (ssVEPs) and retinal structure (assessed qualitatively through outer retinal lamination and apparent thickness via OCT imaging).
Prior to treatment, all children were legally blind from birth, with visual function limited to light perception. Visual acuity following intervention was compared to both baseline and the untreated contralateral eye. Remarkably, 3–4 years after treatment, the visual acuity in the treated eyes improved substantially, while the untreated eyes showed no improvement. OCT imaging following subretinal injection revealed preservation of outer retinal lamination in the treated eyes of three children, supporting the observed functional improvements and suggesting the possibility of sustained protection against retinal degeneration. The safety profile of rAAV8.hRKp.AIPL1 compared favourably with other recombinant AAV vectors used in retinal gene supplementation therapies.
These promising outcomes of gene therapy in young children with AIPL1-associated disease suggest that early intervention in other genetic retinal diseases might provide the greatest potential for benefit.
References:
- Michaelides M, Laich Y, Wong SC, et al. Gene therapy in children with AIPL1-associated severe retinal dystrophy: an open-label, first-in-human interventional study. Lancet. 2025;405:648–57.
Disclosures: This article was created by the touchOPHTHALMOLOGY team utilizing AI as an editorial tool (ChatGPT (GPT-4o) [Large language model]. https://chat.openai.com/chat.) The content was developed and edited by human editors. No funding was received in the publication of this article.
Citation: Revolutionary gene therapy restores vision in children with Leber Congenital Amaurosis type 4. touchOPHTHALMOLOGY.com. Published 23 May 2025.
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