Journal of molecular medicine (Berlin, Germany) · 2018
Cell-specific gene therapy driven by an optimized hypoxia-regulated vector reduces choroidal neovascularization.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Biswal Manas R, Prentice Howard M, Smith George W, Zhu Ping, Tong Yao, Dorey C Kathleen, Lewin Alfred S, Blanks Janet C
Аннотация
UNLABELLED: Aberrant growth of blood vessels in the choroid layer of the eye, termed choroidal neovascularization (CNV), is the pathological hallmark of exudative age-related macular degeneration (AMD), causing irreversible blindness among the elderly. Co-localization of proangiogenic factors and hypoxia inducible factors (HIF) in neovascular membranes from AMD eyes suggests the role of hypoxia in pathogenesis of CNV. In order to utilize hypoxic conditions in RPE for therapeutic purposes, we developed an optimized hypoxia regulated, RPE cell-specific gene therapy to inhibit choroidal neovascularization. An adeno-associated virus (AAV2) vector comprising a RPE-specific promoter and HIF-1 response elements (HRE) was designed to regulate production of human endostatin (a powerful angiostatic protein) in RPE. The vector was tested in a mouse model of laser-induced CNV using subretinal delivery. Spectral domain optical coherence tomography (SD-OCT) images from live mice and confocal images from lectin stained RPE flat mount sections demonstrated reduction in CNV areas by 80% compared to untreated eyes. Quantitative real-time polymerase chain reaction (qPCR) confirmed exogenous endostatin mRNA expression from the regulated vector that was significantly elevated 3, 7, and 14 days following laser treatment, but its expression was completely shut off after 45 days. Thus, RPE-specific, hypoxia-regulated delivery of anti-angiogenic proteins could be a valuable therapeutic approach to treat neovascular AMD at the time and in the ocular space where it arises.
KEY POINTS: An optimized gene therapy vector targeting hypoxia and tissue-specific expression has been designed. The inhibitory role of gene therapy vector was tested in a mouse model of laser-induced CNV. An 80% reduction in choroidal neovascularization was achieved by the optimized vector. The expression of endostatin was limited to retinal pigment epithelium and regulated by hypoxia.
KEY POINTS: An optimized gene therapy vector targeting hypoxia and tissue-specific expression has been designed. The inhibitory role of gene therapy vector was tested in a mouse model of laser-induced CNV. An 80% reduction in choroidal neovascularization was achieved by the optimized vector. The expression of endostatin was limited to retinal pigment epithelium and regulated by hypoxia.