Intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections are currently considered the standard of care for the treatment of exudative age-related macular degeneration (AMD). Anti-VEGF agents have been shown in multiple randomized controlled clinical trials to be associated with vision stabilization or improvement in most patients in the short term.1-3 However, intravitreal anti-VEGF therapy is associated with a variety of burdens, including the risks of repeated intravitreal injections, the need for frequent retreatments, and high costs to the health system.
In addition, the vision gains observed in the first 2 years may be lost when treatment is administered on a pro re nata (PRN) or treat-and-extend regimen.4 While definitive reasons for the visual loss after 2 years are not known, possible causes include undertreatment, or the development of disciform scarring and geographic atrophy.
Gene therapy may be one method to both reduce the logistical and risk burdens of frequent intravitreal injections and avoid undertreatment. The eye is well suited to gene therapy. The eye is both small and easily accessible, allowing precise, localized delivery of a small dose of therapy. This may minimize systemic side effects. Ocular structures also can be examined directly, which allows precise monitoring of the effects of therapy. In addition, the inside of the eye is considered immune-privileged, which reduces the probability of the immune system interacting with the therapy.
Pioneering work in Leber congenital amaurosis by Jean Bennett, MD, PhD, and the National Eye Institute has shown that, by using the adeno-associated virus serotype 2 (AAV2) vector, genes can be delivered to a targeted cell, such as the retinal pigment epithelium.5 Building on this work, researchers at Avalanche Biotechnologies Inc. (Menlo Park, CA) are investigating an AAV2 vector harboring a gene that encodes the soluble fms-like tyrosine kinase-1 (sFLT-1) protein for treatment of exudative AMD. The sFLT-1 is also known as VEGF receptor 1 (VEGFR-1), and is the only known endogenous VEGF inhibitor in the body.
This protein contains six immunoglobulin-like loops, and it is the second binding domain (D2) that is responsible for binding to VEGF. Interestingly, this D2 binding domain is also used in the fusion with IgG1Fc to create aflibercept (Regeneron Pharmaceuticals, Tarrytown, NY), an intravitreal anti-VEGF agent used commonly in clinical practice.
Avalanche Biotechnologies’ phase I trial was conducted in Australia where the technology was developed.6 The study included eight eyes with a history of exudative AMD that were treated previously with anti-VEGF injections. In the study, all eyes were treated with intravitreal ranibizumab at day 0. Seven days later, six eyes received subretinal delivery of the vector using 23-gauge vitrectomy with a 41-gauge cannula, while two eyes served as controls.
A second intravitreal ranibizumab injection was administered to all eyes at week 4, and eyes were then examined monthly for 12 months and assessed for the need for ranibizumab retreatment based on pre-specified criteria demonstrating exudative AMD activity. Retreatment criteria included vision loss attributable to choroidal neovascularization (CNV), fluid observed on optical coherence tomography, or increased CNV leakage on fluorescein angiography. The study met the primary safety endpoint with no drug-related ocular or systemic serious adverse events, including no detectable drug outside of the injected eye. In addition, the results showed evidence of biologic activity of the drug.
While visual acuity is often not demonstrative of true efficacy in an early phase trial, five of the six eyes treated with AAV2-sFLT-1 gained vision. Mean letters of vision improvement was +8.7 in the low dose group, and +6.3 in the high dose group (mean letters of vision loss was -3.5 letters in the control group). The range of visual acuity change was +6 to +13 letters in the low dose AAV2-sFLT-1 group, -6 to +15 letters in the high dose AAV2-sFLT-1 group, and -7 to 0 in the control group. However, these eyes had poor visual acuity at baseline and, therefore, interpreting the impact of AAV2-sFLT-1 on visual acuity change was difficult.
In an early phase trial, anatomic outcomes are often more indicative of a true biologic effect than functional outcomes. It is encouraging that only two of the six vector-treated eyes required a repeat ranibizumab injection over 12 months, and only one injection was needed for each of these eyes. This suggests the treatment exerted a biological effect over a sustained period of time. In the control group, one eye received five retreatment ranibizumab injections and the other eye received one retreatment ranibizumab injection.
A phase 2a study of 32 eyes is currently ongoing in Australia with the results expected in mid-2015. Enrollment into a phase 2b multicenter trial in the United States is expected to begin in late 2015.
Several other methods of extended delivery of anti-VEGF therapy are also undergoing evaluation by several companies (e.g., ForSight Labs, Menlo Park, CA; and Neurotech Pharmaceuticals, Cumberland, RI). The high level of interest emphasizes the importance of developing a method for extended delivery of intraocular treatments. Gene therapy is one approach we will be watching closely.
1. Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431.
2. Brown DM, Michel M, Kaiser PK, Heier JS, Sy JP, Ianchulev T; ANCHOR Study Group. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR Study. Ophthalmology. 2009;116:57-65.e5.
3. The CATT Research Group; Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011 May 19;364:1897-1908.
4. Rofagha S, Bhisitkul RB, Boyer DS, Sadda SR, Zhang K; SEVEN-UP Study Group. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmology. 2013;120: 2292-2299.
5. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s congenital amarousis. N Engl J Med. 2008;358:2240-2248.
6. Rakoczy EP, Lai M, Magno AL, et al. One year follow-up report on the rAAV.sFlt-1 phase I gene therapy trial for exudative age-related macular degeneration. Invest Ophthalmol Vis Sci. 2014;55:E-abstract 1309.
About our author(s):
David R. Lally, MD
Ophthalmic Consultants of
Boston and the New England
Eye Center, Boston
Jeffrey S. Heier, MD
Director of Vitreoretinal Service,
Ophthalmic Consultants of