Multiple gene therapy as a tool for regulating the expression of molecules involved in neovascular age-related macular degeneration

Anti-vascular endothelial growth factor (VEGF) therapies have revolutionized the treatment of neovascular age-related macular degeneration (nAMD) and other retinal diseases. However, the necessity for repeated intravitreal injections and the observation of variable treatment responses calls for new treatment modalities where fewer and more effective interventions can result in a clinical effect. Gene therapy might be such an alternative, and therefore the development and clinical application of gene therapy aimed at modifying gene expression has received considerable attention. The article reviews current knowledge of the background, pathophysiological mechanisms, technologies, limitations, and future directions for gene therapy aimed at modifying the synthesis of compounds involved in acquired and senescent retinal disease. The authors have contributed to the field by developing gene therapy to reduce the expression of vascular endothelial growth factor (VEGF), as well as multiple gene therapy for simultaneous downregulation of the synthesis of VEGF and upregulation of pigment epithelium-derived factor (PEDF) using adeno-associated virus (AAV) vectors. It is suggested that such multi-target gene therapy might be included in future treatments of retinal diseases where the underlying mechanisms are complex and cannot be attributed to one specific mediator. Such diseases might include dry AMD (dAMD) with geographic atrophy, but also diabetic macular edema (DME) and retinal vein occlusion (RVO). Gene therapy can be expected to be most beneficial for the patients in need of multiple intra-vitreal injections and in whom the therapeutic response is insufficient. It is concluded, that in parallel with basic research, there is a need for clinical studies aimed at identifying factors that can be used to identify patients who will benefit from gene therapy already at the time of diagnosis of the retinal disease. • Gene therapy has been developed for the treatment of monogenic retinal diseases such as retinal pigment epithelium (RPE)65-related retinitis pigmentosa, and a number of clinical trials are ongoing with gene therapy targeting other inherited retinal dystrophies. • There is a potential for translating the experience from the replacement of pathological genes in monogenic retinal diseases to the transferal of genes that change the expression of molecules involved in the pathogenesis of acquired and senescent retinal disease. • The authors have used gene therapy to inhibit the synthesis of vascular endothelial growth factor (VEGF) with a subsequent inhibition of experimental subretinal neovascularisations in small rodents and pigs, and the results are being translated to experiments on human tissue. • The authors have introduced the simultaneous transferal of genes targeting the synthesis of more than one protein involved in the pathogenesis of retinal disease. This may become important for the treatment of diseases where the disease development cannot be referred to one single compound. • The exploitation of the benefits of gene therapy requires an identification of the patients in whom the current treatment is ineffective or in whom treatments should be given repeatedly with an accumulated risk of adverse events that is too high.