Journal Article

Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trial

Lai, Chooi-May, French, Martyn A, Degli-Esposti, Mariapia A, Rakoczy, Elizabeth P, Pierce, Cora M, Wikstrom, Matthew E, Chalberg, Thomas W, Magno, Aaron L, Schwartz, Steven D, Blumenkranz, Mark S, Constable, Ian J

2015

Overview

Neovascular, or wet, age-related macular degeneration causes central vision loss and represents a major health problem in elderly people, and is currently treated with frequent intraocular injections of anti-VEGF protein. Gene therapy might enable long-term anti-VEGF therapy from a single treatment. We tested the safety of rAAV.sFLT-1 in treatment of wet age-related macular degeneration with a single subretinal injection. In this single-centre, phase 1, randomised controlled trial, we enrolled patients with wet age-related macular degeneration at the Lions Eye Institute and the Sir Charles Gairdner Hospital (Nedlands, WA, Australia). Eligible patients had to be aged 65 years or older, have age-related macular degeneration secondary to active subfoveal choroidal neovascularisation, with best corrected visual acuity (BCVA) of 3/60–6/24 and 6/60 or better in the other eye. Patients were randomly assigned (3:1) to receive either 1 × 1010 vector genomes (vg; low-dose rAAV.sFLT-1 group) or 1 × 1011 vg (high-dose rAAV.sFLT-1 group), or no gene-therapy treatment (control group). Randomisation was done by sequential group assignment. All patients and investigators were unmasked. Staff doing the assessments were masked to the study group at study visits. All patients received ranibizumab at baseline and week 4, and rescue treatment during follow-up based on prespecified criteria including BCVA measured on the Early Treatment Diabetic Retinopathy Study (EDTRS) scale, optical coherence tomography, and fluorescein angiography. The primary endpoint was ocular and systemic safety. This trial is registered with ClinicalTrials.gov, number NCT01494805. From Dec 16, 2011, to April 5, 2012, we enrolled nine patients of whom eight were randomly assigned to receive either intervention (three patients in the low-dose rAAV.sFLT-1 group and three patients in the high-dose rAAV.sFLT-1 group) or no treatment (two patients in the control group). Subretinal injection of rAAV.sFLT-1 was highly reproducible. No drug-related adverse events were noted; procedure-related adverse events (subconjunctival or subretinal haemorrhage and mild cell debris in the anterior vitreous) were generally mild and self-resolving. There was no evidence of chorioretinal atrophy. Clinical laboratory assessments generally remained unchanged from baseline. Four (67%) of six patients in the treatment group required zero rescue injections, and the other two (33%) required only one rescue injection each. rAAV.sFLT-1 was safe and well tolerated. These results support ocular gene therapy as a potential long-term treatment option for wet age-related macular degeneration. National Health and Medical Research Council of Australia, Richard Pearce Bequest, Lions Save Sight Foundation, Brian King Fellowship, and Avalanche Biotechnologies, Inc.

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Acuity / Adenoviridae / Adverse events / Age / Age related diseases / Aged / Aged, 80 and over / Angiogenesis Inhibitors - administration & dosage / Angiogenesis Inhibitors - adverse effects / Angiography / Assessments / Atrophy / Biotechnology / Choroidal Neovascularization - complications / Choroidal Neovascularization - physiopathology / Choroidal Neovascularization - therapy / Clinical trials / Congenital diseases / Diabetes mellitus / Disease / Expression vectors / Eye / Eye diseases / Female / Gene therapy / Genetic Therapy - adverse effects / Genetic Therapy - methods / Genetic Vectors - administration & dosage / Genetic Vectors - adverse effects / Health services / Hemorrhage / Humans / Immunoglobulins / Injection / Injections, Intraocular / Internal Medicine / Macular degeneration / Male / Medical research / Older people / Patient safety / Patients / Proteins / Randomization / Ranibizumab - administration & dosage / Ranibizumab - adverse effects / Recombinant Proteins / Retinopathy / Vascular endothelial growth factor / Vascular Endothelial Growth Factor Receptor-1 - administration & dosage / Vascular Endothelial Growth Factor Receptor-1 - adverse effects / Vectors (Biology) / Visual Acuity / Wet Macular Degeneration - etiology / Wet Macular Degeneration - physiopathology / Wet Macular Degeneration - therapy