The Asia-Pacific Journal of Ophthalmology

Asia-Pacific Journal of Ophthalmology:

Issue 4, July/August 2016 Review Article

Gene Therapy for Age-Related Macular Degeneration

Constable, Ian Jeffery; Blumenkranz, Mark Scott; Schwartz, Steven D.; Barone, Sam; Lai, Chooi-May; Rakoczy, Elizabeth Piroska

Author Information

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.

Reprints: Ian Jeffery Constable, FRANZCO, Lions Eye Institute, 2 Verdun St, Nedlands,Western Australia, 6009 Australia. E-mail:


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 × 1010 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 × 1011 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.

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