The Lancet最新文献_第2页

Gene therapy in children with AIPL1-associated severe retinal dystrophy: an open-label, first-in-human interventional study

The Lancet Pub Date : 2025-02-20 DOI: 10.1016/s0140-6736(24)02812-5

Michel Michaelides, Yannik Laich, Sui Chien Wong, Ngozi Oluonye, Serena Zaman, Neruban Kumaran, Angelos Kalitzeos, Harry Petrushkin, Michalis Georgiou, Vijay Tailor, Marc Pabst, Kim Staeubli, Roni O Maimon-Mor, Peter R Jones, Steven H Scholte, Anastasios Georgiadis, Jacqueline van der Spuy, Stuart Naylor, Alexandria Forbes, Tessa M Dekker, James W B Bainbridge

{"title":"Gene therapy in children with AIPL1-associated severe retinal dystrophy: an open-label, first-in-human interventional study","authors":"Michel Michaelides, Yannik Laich, Sui Chien Wong, Ngozi Oluonye, Serena Zaman, Neruban Kumaran, Angelos Kalitzeos, Harry Petrushkin, Michalis Georgiou, Vijay Tailor, Marc Pabst, Kim Staeubli, Roni O Maimon-Mor, Peter R Jones, Steven H Scholte, Anastasios Georgiadis, Jacqueline van der Spuy, Stuart Naylor, Alexandria Forbes, Tessa M Dekker, James W B Bainbridge","doi":"10.1016/s0140-6736(24)02812-5","DOIUrl":"https://doi.org/10.1016/s0140-6736(24)02812-5","url":null,"abstract":"<h3>Background</h3>Retinal dystrophy caused by genetic deficiency of <em>AIPL1</em> causes severe and rapidly progressive impairment of sight from birth. We sought to evaluate whether early intervention by gene supplementation therapy was safe and could improve outcomes in children with this condition.<h3>Methods</h3>This non-randomised, single-arm, clinical study conducted in the UK involved four children aged 1·0–2·8 years with severe retinal dystrophy associated with biallelic disease-causing sequence variants in <em>AIPL1</em>. We designed a recombinant adeno-associated viral vector comprising the human <em>AIPL1</em> coding sequence driven by a human rhodopsin kinase promoter region (rAAV8.<em>hRKp.AIPL1</em>). The product was manufactured under a Specials Licence from the Medicines and Health products Regulatory Authority (UK) and made available to affected children with local ethics approval. We administered the product to one eye of each child by subretinal injection. The children were prescribed oral prednisolone to protect against harm from inflammation. Outcome measures included visual acuity (as assessed with a novel touchscreen test), functional vision (assessed by observing and recording the children's visual behaviour and their ability to perform simple vision-guided tasks), visual evoked potentials (assessed by recording cortical electrophysiological responses to full-screen black-and-white flickering stimuli), and retinal structure (assessed with handheld optical coherence tomography [OCT] and widefield fundus imaging). To identify adverse effects, including inflammation and retinal detachment, we conducted ocular examinations using slit-lamp biomicroscopy and dilated fundoscopy. Safety was further assessed by testing of visual acuity, ophthalmoscopy, handheld OCT and widefield fundus imaging.<h3>Findings</h3>Patients were selected for treatment between July 12, 2019, and March 16, 2020. Before intervention, the children's binocular visual acuities were limited to perception of light. At a mean of 3·5 years (range 3·0–4·1) after intervention, the visual acuities of the children's treated eyes had improved to a mean of 0·9 logarithm of the minimal angle of the minimum angle of resolution ([logMAR] range 0·8–1·0); visual acuities before intervention were equivalent to 2·7 logMAR. In contrast, the visual acuities of the children's untreated eyes became unmeasurable at the final follow-up. In the two children able to comply with testing, an objective test of visual acuity confirmed improvements in visual function, and measurement of visual evoked potentials showed enhanced activity of the visual cortex, specific to the treated eyes. In three of the children, structural lamination of the outer retina was better preserved in the treated eye than in the untreated eye, and, for all four children, retinal thickness appeared better preserved in the treated eye than in the untreated eye. The treated eye of one child developed cystoid macula","PeriodicalId":22898,"journal":{"name":"The Lancet","volume":"183 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}