medwireNews: Early intervention with gene therapy may improve visual acuity and functional vision in children with AIPL1-associated severe retinal dystrophy, suggest findings from a first-in-human study published in The Lancet.
Michel Michaelides, from University College London, UK, and colleagues evaluated the safety and efficacy of rAAV8.hRKp.AIPL1 – a recombinant adeno-associated viral vector carrying the human AIPL1 gene driven by a human rhodopsin kinase promoter – in two girls and two boys aged 1.0 to 2.8 years.
Each child had mutations in the AIPL1 gene causing retinal dystrophy, with evidence of preserved outer retinal structure on optical coherence tomography (OCT) before treatment. Their visual acuity was limited to light perception up to distances ranging from 10 to 50 cm.
The children received subretinal injection of rAAV8.hRKp.AIPL1 0.1–0.4 mL vector suspension in the better seeing eye, with the untreated eye serving as a control. The gene therapy was delivered at a titre of 1 × 10¹¹ vector genomes per mL via vitrectomy under general anesthesia. To protect against inflammation, oral prednisolone 1.0 mg/kg was administered for 5 days before surgery and 1 week after, then tapered over the following 4 weeks.
At a mean follow-up of 3.5 years, the treated eyes of the children showed marked improvements in visual acuity assessed using touchscreen tests, functional vision in terms of the ability to fix, follow, and reach objects, and steady-state visually evoked potentials (ssVEPs) in response to stimulus flicker frequency. By contrast, the visual acuity of the untreated eyes was unmeasurable at this timepoint.
Specifically, visual acuity assessed using Cardiff acuity cards improved in the treated eyes from an equivalent 2.7 logMAR at baseline to a mean of 0.9 logMAR (range 0.8–10.0 logMAR).
In the two children who were able to complete the tablet-based PopCSF contrast sensitivity function test, performance was significantly better in treated than untreated eyes. For example, success rates at low frequency (1.5–2.5 cpd) ranged from 24% to 41% in the treated eyes, which was significantly higher than the 10% chance level, compared with 2.4% to 9.3% in the untreated eyes, which equates to no more than would be expected by chance.
“The outcomes observed for the treated eyes would not be expected from the natural history of AIPL1-associated severe retinal dystrophy, which is characterised by rapid, inexorable progression, with visual acuity better than 1.5 logMAR being exceptional for individuals with this condition,” observe the researchers.
The improvements in visual acuity were accompanied by “enhanced activity of the visual cortex specific to the treated eyes,” comment the investigators, with significantly higher response amplitudes on cortical ssVEPs of 0.0467–0.087 μV², compared with 0.006–0.008 μV² in untreated eyes.
“Together, these results provide objective evidence of a substantial benefit to visual function involving higher visual pathways,” says the team.
Parents also reported notable improvements in their children's visual behavior, including better object tracking, recognition of faces and colors, improved mobility and coordination, and reduced light-staring and nystagmus.
Structural imaging with optical coherence tomography further demonstrated "relative preservation of outer retinal lamination in the treated eyes of three children at the ages of 4.5 years, 5.0 years, and 6.2 years," the authors report, suggesting long-term benefit against progressive degeneration. They add that “[i]ntervention even earlier in infancy might result in greater protection of retinal architecture and greater potential for lasting benefit.”
There were no serious adverse events. One child developed cystoid macular edema in the treated eye, which partially resolved by the final follow-up and did not impact visual function gains.
In a linked commentary, Artur Cideciyan and Tomas Aleman, both from the University of Pennsylvania in Philadelphia, USA, note that "the challenges of measurement of vision in preschool-aged children are multiplied when vision loss is severe, making objective readouts of visual function desirable in clinical trials."
Nevertheless, they write that “[a]lthough this intervention did not conform to the rigours of a clinical trial, the results provide important information to address the challenges of treating rare and severe paediatric inherited retinal dystrophies.”
The study authors conclude: “[W]e are now administering sequential bilateral gene therapy to affected young children under a Specials Licence and exploring the feasibility of making the product more widely available.
“This could mean an improvement in neurodevelopment and social behaviour and provide lifelong psychosocial benefit for children affected by this retinal dystrophy.”
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