Health 18/03/2025 00:05

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

Retinal dystrophy caused by genetic deficiency of AIPL1 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.

Methods

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 AIPL1. We designed a recombinant adeno-associated viral vector comprising the human AIPL1 coding sequence driven by a human rhodopsin kinase promoter region (rAAV8.hRKp.AIPL1). 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.

Findings

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 macular oedema. No other safety concerns were identified.

Interpretation

Our findings indicate that young children with AIPL1-related retinal dystrophy benefited substantially from subretinal administration of rAAV8.hRKp.AIPL1, with improved visual acuity and functional vision and evidence of some protection against progressive retinal degeneration, without serious adverse effects.

Funding

UK National Institute for Health Research and Moorfields Eye Charity.
 
 
 

Introduction

Early-onset inherited retinal dystrophies cause severe sight impairment in infants, with congenital nystagmus, impaired pupil responses, and severely reduced responses on electroretinography.1,2 The prevalence of early-onset rod-cone dystrophies is estimated to be one to three in 100 000.3,4 At least 26 different genes have been implicated to date,5 with mutations in CEP290GUCY2DCRB1, and RPE65 among the most common causes.5 With the exception of RPE65-related disease, for which adeno-associated virus (AAV)-mediated gene therapy (with voretigene neparvovec) can improve vision-guided mobility in low luminance conditions,6 no specific treatment is available.5
Research in context
Evidence before this study
We searched PubMed and MEDLINE for studies published between Jan 1, 2000, and June 30, 2019, that addressed AIPL1-associated severe retinal dystrophy, using search terms “AIPL1”, “Leber congenital amaurosis”, “retinal degeneration”, and “gene therapy”. There were no language restrictions. Preclinical studies of gene therapy in Aipl1-deficient mouse models reported partial restoration of retinal structure and function. Gene therapy in affected children had not been reported.
Added value of this study
This first-in-human interventional study of gene therapy for children with AIPL1-associated severe retinal dystrophy showed that early intervention with gene supplementation can substantially improve visual acuity and functional vision outcomes. Structural preservation of the retina in the treated eyes suggests protection against progressive retinal degeneration.
Implications of all the available evidence
AIPL1-associated severe retinal dystrophy is an ultra-rare cause of severe sight impairment from birth with no existing treatment. Adeno-associated viral-mediated gene supplementation therapy at an early age can markedly improve visual acuity and functional vision and preserve retinal structure. Gene therapy to address severe impairment of sight in early childhood promises lasting benefit for neurodevelopment. The positive outcomes of gene therapy in young children with AIPL1-associated disease imply that early intervention in other genetic retinal diseases might provide the greatest potential for benefit.
Variants in the gene encoding AIPL1 account for up to 5% of infants affected by early-onset rod-cone dystrophy. AIPL1 is expressed in rod and cone photoreceptor cells during development, and the encoded protein plays a crucial role in phototransduction.7–9 AIPL1 is a specialised molecular co-chaperone for cGMP-specific PDE6, supporting the stability, assembly and catalytic activity of PDE6 in cones and rods.9 In Aipl1−/− mice, the absence of Aipl1 is associated with reduced concentrations of PDE6, elevated concentrations of cGMP, and rapid degeneration of photoreceptor cells.10,11 Similarly, AIPL1-knockout and patient-derived human retinal organoid models are characterised by a reduction in PDE6 and elevation in cGMP.12–14
Infants with disease-causing variants in AIPL1 are affected by severe and rapidly progressive impairment of sight from birth. In a cross-sectional survey including 42 individuals aged between 6 months and 43 years with AIPL1-related retinal dystrophy, the sight of the affected individuals was limited to perception of light;15 only exceptionally was visual acuity better than 1·5 logarithm of the minimal angle of the minimum angle of resolution (logMAR). Optical coherence tomography (OCT) imaging identified relative preservation of outer retinal structure at the fovea only in children younger than 4 years. This preservation of viable foveal photoreceptor cells in early life indicates a window of opportunity for potential benefit by gene supplementation therapy.15 In Aipl1−/− mice, gene supplementation with human or mouse cDNA by subretinal injection of recombinant AAV (rAAV) vectors (rAAV2-CMV-AIPL1, rAAV2-CMV-Aipl1, and rAAV8-CMV-Aipl1) improved retinal function as measured by scotopic and photopic electroretinography and preserved thickness of the retinal outer nuclear layer.16 Furthermore, treatment of AIPL1 gene knockout and patient-derived retinal organoids with rAAV expressing AIPL1 cDNA under the control of the human GRK1 promoter rescued expression levels of PDE6 and cGMP.12 Here, we describe the outcomes following rAAV-mediated gene supplementation therapy in four young children with AIPL1-deficiency.

Methods

Study design

rAAV8.hRKp.AIPL1 is a recombinant AAV vector, comprising a human GRK1 promoter region driving the human AIPL1 coding sequence. In the absence of a clinical trial, we made this innovative experimental product available to children with confirmed mutations in AIPL1 under a Specials Licence with the approval of the Paediatric Bioethics Service at Great Ormond Street Hospital for Children (GOSH GMOSC #7).17,18,19 This non-randomised, single-arm, open-label, first-in-human interventional study was done at Moorfields Eye Hospital (London, UK) and Great Ormond Street Hospital for Children (London, UK).

Participants

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 were considered for treatment. As the ethics approval was limited to four children, we offered treatment to the first four children who satisfied the eligibility criteria. If a difference in visual function between the patients’ eyes could be identified, the better-seeing eye was selected for treatment. The contralateral eye remained untreated for safety. The parents of each child provided fully informed written consent for treatment.

Procedures

rAAV8.hRKp.AIPL1 was produced at University College London's Wolfson Gene Therapy Unit using three-plasmid transfection in HEK293T cells according to Good Manufacturing Practice guidelines, under a Manufacturer Specials Licence from the UK Medicines and Health products Regulatory Authority. MeiraGTx (holder of a Specials Licence) supported production, storage, quality assurance, and dispensing. 0·1–0·4 mL AAV2/8.hRKp.AIPL1 vector suspension was administered at a titre of 1 × 1011 vector genomes per mL during vitrectomy surgery under general anaesthesia (appendix pp 1–2). The suspension was delivered subretinally to establish a bleb extending across the posterior pole of the retina from the superotemporal vascular arcade to the inferotemporal arcade, encompassing the surviving central macula. To protect against harm from inflammation, children were prescribed oral prednisolone at a dose of 1·0 mg/kg bodyweight daily for 5 days before surgery and 1 mg/kg for the first week after surgery, with tapering of the dose for a further 4 weeks (appendix p 1). We evaluated the children's functional vision, visual acuity, and retinal structure before intervention and twice subsequently. Functional vision was tested by observing and recording the children's visual behaviour and their ability to do simple vision-guided tasks. For example, the children were tasked with locating by sight white objects of a range of sizes in turn, against a dark background under normal office illumination, and with moving crayons between cups; they were also invited to draw on paper. When possible, treated and untreated eyes were tested independently in the same way. Children were also asked to mobilise along a normally lit corridor with the use of both eyes together and to identify doorways. Visual acuity tests were selected according to the age and ability of each child at the time of testing. We assessed visual acuity subjectively with standard age-appropriate recognition tasks (including Cardiff acuity cards, Kay pictures, and the Sonksen logMAR test using Sheridan Gardiner letters); when visual acuity could not be measured using these methods, we tested the children's ability to perceive and follow a pen torch light source at distances ranging from 5 cm to 50 cm. Near visual acuity was also measured in one child with single optotypes of the Sonksen logMAR test. logMAR equivalent values were obtained from the individual tests (eg, Cardiff acuity cards have a logMAR equivalent value, and the Kay picture test is developed using a logMAR scoring system). A logMAR score of 0·0 indicates perfect acuity; 1·3 indicates severe sight impairment; and 2·7 indicates perception of light only. Visual acuity was assessed objectively with a novel contrast sensitivity function (CSF) touchscreen test, the PopCSF test (appendix p 3; figure 1).20,21 For the PopCSF test, 100% contrast targets were categorised on the basis of their spatial frequency: low (1·5–2·5 cycles per degree [cpd]), medium (2·5–3·5 cpd), and high (>3·5 cpd). Six additional children with AIPL1-associated severe retinal dystrophy (aged 2·9–3·9 years) were recruited and tested monocularly or binocularly with the popCSF test at Moorfields Eye Hospital, offering a benchmark for untreated performance. We evaluated visual signal detection in the visual cortex by recording cortical electrophysiological responses to full-screen black-and-white flickering stimuli and flickering (contrast-reversing) gratings across a range of spatial frequencies (steady-state visually evoked potential [ssVEP] technique; appendix pp 3–5; figure 1). The children's parents were also asked to monitor for signs of discomfort and any changes in the children's functional vision as they occurred; their observations were recorded in the clinical notes. Retinal imaging was done with handheld OCT and widefield fundus imaging (appendix p 5). Ocular examinations, including slit-lamp biomicroscopy and dilated fundoscopy, were done to identify adverse effects such as inflammation and retinal detachment. Safety was assessed by testing of visual acuity (as unexpected deterioration of visual acuity can indicate an adverse event or in itself be an adverse event), ophthalmoscopy, handheld OCT, and widefield fundus imaging.
 

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