Fast track — ArticlesAge-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial
Introduction
One of the most severe forms of inherited retinal degeneration is Leber's congenital amaurosis, which is a group of diseases that are caused by mutations in any of 13 genes. Patients with Leber's congenital amaurosis have severe loss of vision and abnormal eye movements (nystagmus) in early infancy and childhood. Diminished pupillary light reflexes and flat or nearly undetectable responses during electroretinography confirm the clinical diagnosis.1, 2, 3, 4 Type 2 Leber's congenital amaurosis, caused by mutations in a gene that encodes a protein needed for the isomerohydrolase activity of the retinal pigment epithelium (RPE65), accounts for about 6% of cases.5 There is no treatment for Leber's congenital amaurosis and severe visual impairment during childhood usually progresses to total blindness by the third or fourth decade of life.4 Clues for how to treat type 2 disease came from studies in which mutations in RPE65 resulted in substantially diminished amounts of 11-cis retinal.6, 7, 8, 9
Replication-deficient adeno-associated virus (AAV)-mediated delivery of the wildtype RPE65 cDNA to the RPE in animal models of Leber's congenital amaurosis resulted in rapid development of retinal and visual function through the enzyme-mediated generation of 11-cis retinal.10 Furthermore, the success rate for recovery and magnitude of improvement was related to the age at treatment, with best results obtained in young animals before widespread cellular degeneration.11, 12 This result and additional findings for safety and efficacy13 provided the basis for a phase 1 trial of gene augmentation therapy in individuals with RPE65-associated Leber's congenital amaurosis, and for the inclusion of children who might get the most benefit from the intervention.14 AAV-mediated RPE65 therapy in young adults15, 16, 17, 18, 19, 20 resulted in most individuals reporting a perception of increased brightness in the injected eye after treatment, as judged with various methods, including dark adaptometry, perimetry, and pupillary light reflexes.15, 16, 17, 18 Two individuals in two studies15, 16 showed improvements in ambulation. Significant improvements in visual acuity in all three individuals were reported in one study.15
Here we present the results from the complete phase 1 dose-escalation study done at the Children's Hospital of Philadelphia (CHOP, PA, USA) with the aim to assess the safety and efficacy of AAV2-hRPE65v2.15 We also assessed the role of an individual's age (or stage of disease progression) on the extent of reversal of blindness.
Section snippets
Patients
Inclusion and exclusion criteria for patients are reported by Maguire and colleagues.15 12 patients (aged 8–44 years) with RPE65-associated Leber's congenital amaurosis were enrolled and consecutively treated, with an interval of at least 6 weeks between individuals (table). All surgery was done at CHOP and follow-up tests were done at CHOP or Seconda Università degli Studi di Napoli (Naples, Italy) for the Italian patients (webappendix pp 1–2 and 6–8). 20 age-matched normal-sighted male and
Results
Maguire and colleagues15 have described the short-term results from the first three patients (NP01, NP02, and NP03 in the low-dose cohort). The vector was injected into the macula in nine patients, but not in three patients (NP01,15 CH12, CH13) with substantial atrophy in this region. About half the macula was exposed in patient NP15 (figure 1). An epiretinal membrane that was noted during baseline studies in the injected eye of patient CH10 was removed before injection. A foveal dehiscence was
Discussion
All 12 patients given AAV2-hRPE65v2 in one eye showed improvement in retinal function. The effect was stable during follow-up. The results support our hypothesis that the response to subretinal gene therapy depends on the extent of retinal degeneration and, therefore, the age of the patient.14
Assessment of global retinal function showed clinically meaningful vision in patients. The most noteworthy result was the ability of children to navigate an obstacle course independently and accurately,
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