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ABSTRACT
Introduction: In neovascular age related macular degeneration (nAMD), gene therapy to chronically express anti-vascular endothelial growth factor (VEGF) proteins could ameliorate the treatment burden of chronic intravitreal therapy and improve limited visual outcomes associated with ‘real world’ undertreatment.
Areas covered: In this review, the authors assess the evolution of gene therapy for AMD. Adeno-associated virus (AAV) vectors can transduce retinal pigment epithelium; one such early application was a phase I trial of AAV2-delivered pigment epithelium derived factor gene in advanced nAMD. Subsequently, gene therapy for AMD shifted to the investigation of soluble fms-like tyrosine kinase-1 (sFLT-1), an endogenously expressed VEGF inhibitor, binding and neutralizing VEGF-A. After some disappointing results, research has centered on novel vectors, including optimized AAV2, AAV8 and lentivirus, as well as genes encoding other anti-angiogenic proteins, including ranibizumab, aflibercept, angiostatin and endostatin. Also, gene therapy targeting the complement system is being investigated for geographic atrophy due to non-neovascular AMD.
Expert opinion: The success of gene therapy for AMD will depend on the selection of the most appropriate therapeutic protein and its level of chronic expression. Future investigations will center on optimizing vector, promoter and delivery methods, and evaluating the risks of the chronic expression of anti-angiogenic or anti-complement proteins.
Article highlights
In neovascular age related macular degeneration (nAMD), gene therapy could ameliorate the treatment burden associated with chronic intravitreal therapy and has the potential to improve poor visual outcomes associated with ‘real world’ anti-vascular endothelial growth factor (anti-VEGF) undertreatment.
To date, the most common viral vector utilized in retinal genetic therapy is the adeno-associated virus (AAV). The AAV vector has many features making it an excellent vector choice in retinal diseases, including non-integrating nature, low inflammatory potential, low retinal toxicity at appropriate doses, non-pathogenic nature, ability to transduce non-dividing cells, and excellent track record of safety in human trials.
Vector delivery to the target retinal tissue involves two potential methods: intravitreal injection or pars plana vitrectomy (PPV) followed by subretinal injection.
In neovascular AMD (nAMD), gene therapy is being assessed to chronically express anti-angiogenic proteins such as pigment epithelium derived factor (PEDF), fms-like tyrosine kinase-1 (sFLT-1), as well as ranibizumab, aflibercept, angiostatin and endostatin.
In geographic atrophy (GA), gene therapy is being assessed to target the complement system.
The risks of chronic and extensive inhibition of the VEGF pathway are incompletely known and require further assessment.
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Declaration of interest
TA Ciulla has an employment relationship with the Ophthotech Corporation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.