Gene therapy for age-related macular degeneration

Abstract

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.

Advanced glycation end products promote VEGF expression and thus choroidal neovascularization via Cyr61-PI3K/AKT signaling pathway

“…CNV is now known to occur as a final common symptom in nearly 40 ophthalmic diseases, such as age-related macular degeneration (AMD), ocular histoplasmosis, myopic macular degeneration, idiopathic CNV and ocular trauma 1 , 2 . Currently, exploring the detailed mechanism of CNV and the clinical control strategy has become one of hotspots and difficulties in the research field of ophthalmology.…”

IGFBP‑rP1‑silencing promotes hypoxia‑induced angiogenic potential of choroidal endothelial cells via the RAF/MEK/ERK signaling pathway

“…RF/6A cells, a rhesus choroid endothelial cell line widely used in research to simulate ophthalmic micro-endothelial cells and explore the influences of external factors and corresponding mechanisms (15)(16)(17)41,42) were used to observe the influence of IGFBP-rP1-silencing and hypoxia on CNV formation in vitro. rna interference, which allows for the silencing of mammalian genes with great specificity and potency, has been extensively used in several fields to investigate gene functions and design novel therapeutic methods (43)(44)(45)(46)(47)(48). Using this technique, IGFBP-rP1-silencing was successfully accomplished in RF/6A cells.…”

Gene and Cell Therapy for Muscular Dystrophies: Are We Getting There?

“…In the case of the retina or the substantia nigra, direct delivery may be achieved by injecting the vector directly into or near the target. 12 , 13 For a tissue like skeletal muscle, which is distributed throughout the body, a systemic route of delivery is necessary and the predominant one has been intravenous (IV). Although an intra-arterial catheterization is possible and would avoid capillary filters such as the liver or the lung, IV injection has been the preferred route of administration so far, most likely for its simplicity.…”