Cell-specific gene therapy driven by an optimized hypoxia-regulated vector reduces choroidal neovascularization

Abstract

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.

The role of hypoxia-inducible factors in neovascular age-related macular degeneration: a gene therapy perspective

“…Engineering of inducible cell-specific promoters to the administration of exogenous genes for the treatment of nAMD has been proposed [233]. Combining tissue-specific promoters (pRpe65) with HRE regulatory elements, hypoxia-mediated spatial and temporal regulation of angiostatic proteins can be achieved to mitigate CNV in mouse models of nAMD [234].…”

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

“…Hypoxia is considered to serve an important role in CNV formation, a critical characteristic of wet AMD and the main cause of visual impairment in patients with subsequent bleeding or fibrosis (6)(7)(8)(49)(50)(51). CoCl 2 -induced chemical hypoxia, a reliable method of mimicking hypoxia (52)(53)(54)(55), was used to imitate the internal environment during choroidal angiogenesis.…”

Viral-Vector-Delivered Anti-Angiogenic Therapies to the Eye

“…In a rat model of hVEGF, suprachoroidal injection of RGX-314 between the sclera and choroid suppressed VEGF-induced vascular leakage and vasodilation [27]. Oxygen-induced retinopathy in rat, laser induced CNV in mouse AAV2 intravitreal mTOR shRNA, wet AMD, ROP, DR [75][76][77] Laser induced CNV in mouse scAAV2 subretinal endostatin wet AMD [78] Oxygen-induced retinopathy in rat, laser induced CNV in mouse scAAV2 intravitreal, subretinal calreticulin anti-angiogenic domain (CAD) wet AMD, DR [79] Oxygen-induced retinopathy in mouse rAAV intravitreal Kringle1 domain of hepatocyte growth factor (HGFK1) wet AMD, DR [80] Oxygen-induced retinopathy in mouse Adenovirus GV120 intravitreal Galetin-1-RNAinterference ROP [81] Laser induced CNV and oxygen-induced retinopathy in mouse, AAV1-CRISPR/Cas9 intravitreal CRISPR/Cas9 targeted to VEGFR 2 wet AMD, ROP [82] Laser induced CNV in mouse AAV9-CRISPR-LbCpf1 intravitreal CRISPR-LbCpf1 targeted to VEGF A and HIF1α wet AMD [83] Laser induced CNV in mouse Lentivirus subretinal microRNAs targeting VEGF-A wet AMD [62] Laser induced CNV in mouse AAV5 subretinal PEDF, multiple miRNAs targeting the VEGFA gene wet AMD [84] Corneal chemical burn in a rabbit AAV8/9 chimeric capsid (8G9) corneal intrastromal codon optimized human leucocyte antigen G1+ G5 Corneal neovascularization [85] Oxygen-induced retinopathy in rat Lentivirus subretinal shRNAs to VEGFR2 or STAT3 ROP [86] Oxygen-induced retinopathy in rat Lentivirus subretinal VEGF-A or VEGF-A164 shRNA ROP [87] AAV = adeno-associated virus, ADV = adenovirus, AMD = age-related macular degeneration, CNV = choroidal neovascularization, DR = diabetic retinopathy, LV = lentivirus, ROP = retinopathy of prematurity.…”