Results at 5 Years After Gene Therapy for RPE65-Deficient Retinal Dystrophy

Abstract

Previously, results at 2 years after subretinal injection of a recombinant adeno-associated virus vector expressing RPE65 (rAAV2-CB-hRPE65) in eight adults and four children with retinal degeneration caused by RPE65 mutations were reported. Now, results at 5 years after treatment in 11 of these subjects are reported. Subjects received a subretinal injection of rAAV2-CB-hRPE65 in the poorer-seeing eye, at either of two dose levels, and were followed for 5 years after treatment. The primary safety outcomes were ocular and non-ocular adverse events. Efficacy outcomes included changes in best corrected visual acuity, static perimetry hill of vision measurements for the central 30° (V), and total (V) visual field and kinetic perimetry visual field area. The only adverse events reported during years 3, 4, and 5 were minor intercurrent illnesses. Pediatric subjects had improvement in visual acuity and static perimetry in the treated eye, sometimes with a smaller improvement in the untreated eye, during the first 2 years of the study that persisted during years 3-5, with no consistent changes in kinetic perimetry during the study. Most adult subjects had no consistent changes in visual acuity or static perimetry during the study. Three adult subjects with markedly abnormal baseline kinetic visual field area had improvement in the treated eye during the first 1-2 years after treatment, but the absolute magnitude of the improvement was small and was not sustained at subsequent visits. There were no clinically significant adverse events. Visual acuity and static perimetry testing results suggest that treating patients at a younger age is associated with better visual function outcomes during 5 years after treatment.

The effect of human gene therapy for RPE65-associated Leber’s congenital amaurosis on visual function: a systematic review and meta-analysis

“…Subgroup analyses were performed to compare BCVA at baseline of less than or more than 1.3 logMAR based on a recent study which reported that BCVA improvement was different between eyes with a baseline acuity at more than 1.3 logMAR (~20/400) vs. eyes with lower baseline BCVA [11]. Funnel plots were used to screen for potential publication bias.…”

CAPN5 genetic inactivation phenotype supports therapeutic inhibition trials

“…Success in gene therapy for the autosomal recessive disease, specifically the RPE65 Leber Congenital Amaurosis clinical trials in the eye, has shown that gene therapy is an ideal treatment option for patients (Pennesi et al, ; Russell et al, ). However, the delivery of a healthy gene allele is not feasible to treat patients with the autosomal dominant disease.…”

“…Alignments were created by BLAST searches for CAPN5 in different species and then sequence alignments were performed using ClustalW (Thompson, Higgins, & Gibson, ). Sequence alignments were visualized using ESPript 3.0 (Robert & Gouet, ).…”

“…Human gene therapy has gained success for cases of the autosomal recessive disease. These validated gene therapies, such as the first‐ever RPE65 gene therapy clinical trial, supplement diseased genes with wild‐type (WT) copy (Pennesi et al, ; Russell et al, ). However, even the most successful gene supplementation therapy cannot address dominant mutations.…”

10th Royan Institute's International Summer School on “Molecular Biomedicine: From Diagnostics to Therapeutics”

“…The first successful in vivo gene therapy, in which the targeted cells are corrected genetically inside the body, was performed by AAV vectors encoding a functional RPE65 gene for a patient with retinal pigment epithelium deficiency. [ 2 ] In vivo gene therapy has also been accomplished for hemophilia‐B to restore the factor IX production by the liver. Another in vivo gene therapy has been carried out for CNS through peripheral vein infusion of AAV8 vectors containing an optimized codon for UGT1A1.…”