Gene Therapy Intervention in Neovascular Eye Disease: A Recent Update
Authors: Fan-Li Lin, Peng-Yuan Wang, Yu-Fan Chuang, Jiang-Hui Wang, Vickie H.Y. Wong, Bang V. Bui, Guei-Sheung Liu
Journal: Molecular Therapy (2020)

Aberrant growth of blood vessels (neovascularization) is a key feature of severe eye diseases that can cause legal blindness, including neovascular age-related macular degeneration (nAMD) and diabetic retinopathy (DR). The development of anti-vascular endothelial growth factor (VEGF) agents has revolutionized the treatment of ocular neovascularization. Novel proangiogenic targets, such as angiopoietin and platelet-derived growth factor (PDGF), are under development for patients who respond poorly to anti-VEGF therapy and to reduce adverse effects from long-term VEGF inhibition. A rapidly advancing area is gene therapy, which may provide significant therapeutic benefits. Viral vector-mediated transgene delivery provides the potential for continuous production of antiangiogenic proteins, which would avoid the need for repeated anti-VEGF injections. Gene silencing with RNA interference to target ocular angiogenesis has been investigated in clinical trials. Proof-of-concept gene therapy studies using gene-editing tools such as CRISPR-Cas have already been shown to be effective in suppressing neovascularization in animal models, highlighting the therapeutic potential of the system for treatment of aberrant ocular angiogenesis. This review provides updates on the development of anti-VEGF agents and novel antiangiogenic targets. We also summarize current gene therapy strategies already in clinical trials and those with the latest approaches utilizing CRISPR-Cas gene editing against aberrant ocular neovascularization. Aberrant growth of blood vessels (neovascularization) is a key feature of severe eye diseases that can cause legal blindness, including neovascular age-related macular degeneration (nAMD) and diabetic retinopathy (DR). The development of anti-vascular endothelial growth factor (VEGF) agents has revolutionized the treatment of ocular neovascularization. Novel proangiogenic targets, such as angiopoietin and platelet-derived growth factor (PDGF), are under development for patients who respond poorly to anti-VEGF therapy and to reduce adverse effects from long-term VEGF inhibition. A rapidly advancing area is gene therapy, which may provide significant therapeutic benefits. Viral vector-mediated transgene delivery provides the potential for continuous production of antiangiogenic proteins, which would avoid the need for repeated anti-VEGF injections. Gene silencing with RNA interference to target ocular angiogenesis has been investigated in clinical trials. Proof-of-concept gene therapy studies using gene-editing tools such as CRISPR-Cas have already been shown to be effective in suppressing neovascularization in animal models, highlighting the therapeutic potential of the system for treatment of aberrant ocular angiogenesis. This review provides updates on the development of anti-VEGF agents and novel antiangiogenic targets. We also summarize current gene therapy strategies already in clinical trials and those with the latest approaches utilizing CRISPR-Cas gene editing against aberrant ocular neovascularization. Angiogenesis is the formation of new blood vessels from preexisting vasculature, a process regulated by a dynamic balance between endogenous proangiogenic and antiangiogenic factors. Stimuli, such as biomechanical stress, hypoxia, ischemia, immune or inflammatory responses, and genetic variations, can disturb the balance in favor of angiogenesis.1Carmeliet P. Jain R.K. Angiogenesis in cancer and other diseases.Nature. 2000; 407: 249-257Crossref PubMed Scopus (6654) Google Scholar Ocular angiogenesis can occur in the retina, choroid, as well as cornea, and unchecked pathological blood vessel formation (neovascularization) can lead to severe visual impairment. These newly formed blood vessels are exudative, resulting in the accumulation of extracellular fluid subsequent to impairment of retinal function. Moreover, the aberrant growth of new vessels interferes with normal tissue structure and corneal transparency.2Sharif Z. Sharif W. Corneal neovascularization: updates on pathophysiology, investigations & management.Rom. J. Ophthalmol. 2019; 63: 15-22Crossref PubMed Google Scholar,3Witmer A.N. Vrensen G.F. Van Noorden C.J. Schlingemann R.O. Vascular endothelial growth factors and angiogenesis in eye disease.Prog. Retin. Eye Res. 2003; 22: 1-29Crossref PubMed Scopus (699) Google Scholar Neovascularization is associated with a range of ocular disorders, including neovascular age-related macular degeneration (nAMD), diabetic retinopathy (DR), retinopathy of prematurity (ROP), corneal neovascularization, retinal vessel occlusion, and neovascular glaucoma (reviewed in Campochiaro4Campochiaro P.A. Ocular neovascularization.J. Mol. Med. 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