title: Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trial.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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 × 10(10) vector genomes (vg; low-dose rAAV.sFLT-1 group) or 1 × 10(11) 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  National Health and Medical Research Council of Australia, Richard Pearce Bequest, Lions Save Sight Foundation, Brian King Fellowship, and Avalanche Biotechnologies, Inc.
authors.affiliation: Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia; Lions Eye Institute, Nedlands, WA, Australia. Electronic address: elizabeth.rakoczy@uwa.edu.au.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Rakoczy
authors.affiliation: Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia; Lions Eye Institute, Nedlands, WA, Australia.
authors.forename: Chooi-May
authors.initials: CM
authors.lastname: Lai
authors.affiliation: Lions Eye Institute, Nedlands, WA, Australia.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Magno
authors.affiliation: Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia; Lions Eye Institute, Nedlands, WA, Australia.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Wikstrom
authors.affiliation: School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, WA, Australia.
authors.forename: Martyn A
authors.initials: MA
authors.lastname: French
authors.affiliation: Lions Eye Institute, Nedlands, WA, Australia.
authors.forename: Cora M
authors.initials: CM
authors.lastname: Pierce
authors.affiliation: University of California, Los Angeles, CA, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Schwartz
authors.affiliation: Stanford University, Palo Alto, CA, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Blumenkranz
authors.affiliation: Avalanche Biotechnologies, Inc, Menlo Park, CA, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Chalberg
authors.affiliation: Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia; Lions Eye Institute, Nedlands, WA, Australia.
authors.forename: Mariapia A
authors.initials: MA
authors.lastname: Degli-Esposti
authors.affiliation: Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia; Lions Eye Institute, Nedlands, WA, Australia; Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Constable
mesh_terms: D000256:Adenoviridae; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D020256:Choroidal Neovascularization / Q000150:complications / Q000503:physiopathology / Q000628:therapy; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D056965:Injections, Intraocular; D008297:Male; D000069579:Ranibizumab / Q000008:administration & dosage / Q000009:adverse effects; D011994:Recombinant Proteins; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000008:administration & dosage* / Q000009:adverse effects; D014792:Visual Acuity; D057135:Wet Macular Degeneration / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*
chemical_list: D020533:Angiogenesis Inhibitors; D011994:Recombinant Proteins; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D000069579:Ranibizumab