title: Gene Therapy for Age-Related Macular Degeneration.
abstract: The purpose of this article was to evaluate safety and signals of efficacy of gene therapy with subretinal rAAV.sFlt-1 for wet age-related macular degeneration (wet AMD). A phase 1 dose-escalating single-center controlled unmasked human clinical trial was followed up by extension of the protocol to a phase 2A single-center trial. rAAV.sFlt-1 vector was used to deliver a naturally occurring anti-vascular endothelial growth factor agent, sFlt-1, into the subretinal space. In phase 1, step 1 randomized 3 subjects to low-dose rAAV.sFlt-1 (1 × 10 vector genomes) and 1 subject to the control arm; step 2 randomized an additional 3 subjects to treatment with high-dose rAAV.sFlt-1 (1 × 10 vector genomes) and 1 subject to the control arm. Follow-up studies demonstrated that rAAV.sFlt-1 was well tolerated with a favorable safety profile in these elderly subjects with wet AMD. Subretinal injection was highly reproducible, and no drug-related adverse events were reported. Procedure-related adverse events were mild and self-resolving. Two phakic patients developed cataract and underwent cataract surgery. Four of the 6 patients responded better than the small control group in this study and historical controls in terms of maintaining vision and a relatively dry retina with zero ranibizumab retreatments per annum. Two patients required 1 ranibizumab injection over the 52-week follow-up period. rAAV.sFlt-1 gene therapy may prove to be a potential adjunct or alternative to conventional intravitreal injection for patients with wet AMD by providing extended delivery of a naturally occurring antiangiogenic protein.
authors.affiliation: From the *Lions Eye Institute; †Sir Charles Gairdner Hospital, Nedlands; ‡Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, Western Australia, Australia; §University of California Los Angeles, Los Angeles; ¶Byers Eye Institute at Stanford, Palo Alto; and ‖Avalanche Biotechnologies, Inc, Menlo Park, CA.
authors.forename: Ian Jeffery
authors.initials: IJ
authors.lastname: Constable
authors.forename: Mark Scott
authors.initials: MS
authors.lastname: Blumenkranz
authors.forename: Steven D
authors.initials: SD
authors.lastname: Schwartz
authors.forename: Sam
authors.initials: S
authors.lastname: Barone
authors.forename: Chooi-May
authors.initials: CM
authors.lastname: Lai
authors.forename: Elizabeth Piroska
authors.initials: EP
authors.lastname: Rakoczy
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D056965:Injections, Intraocular; D008297:Male; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D014821:Vitrectomy / Q000379:methods; D057135:Wet Macular Degeneration / Q000628:therapy*
chemical_list: D020533:Angiogenesis Inhibitors; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1