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

Abstract

Understanding the mechanisms that underlie age-related macular degeneration (AMD) has led to the identification of key molecules. Hypoxia-inducible transcription factors (HIFs) have been associated with choroidal neovascularization and the progression of AMD into the neovascular clinical phenotype (nAMD). HIFs regulate the expression of multiple growth factors and cytokines involved in angiogenesis and inflammation, hallmarks of nAMD. This knowledge has propelled the development of a new group of therapeutic strategies focused on gene therapy. The present review provides an update on current gene therapies in ocular angiogenesis, particularly nAMD, from both basic and clinical perspectives.

Targeted therapy in age-related macular degeneration (AMD)

“…The second form develops faster and more often leads to total blindness. It is expected that in 2020 the number of patients with AMD will increase to 196 million, and up to 288 million in 2040, due to the aging of the human population [1]. AMD primarily threatens central vision, because the lesions affect the macula.…”

“…Disfunction at the cellular level in AMD may refer to: photoreceptor, retinal pigment epithelial cells (RPE), Bruch's membrane (BM), or choroid. Observed changes are most likely the result of destabilization of reactive oxygen species (ROS), phagocytosis, extracellular matrix remodeling, and alternative complement-related inflammation [1]. Relevant evidence suggests mitochondrial damage and epithelial cell death in AMD pathogenesis, but the effect of mitochondria and humanin G (HNG) is still not fully understood.…”

“…Regarding dry AMD, treatment is very limited. In clinical practice, almost only palliative antioxidant therapy is used in different forms, which delays progression in 20-25% of patients [1]. The efficacy of using the intravitreal anti-vascular endothelial growth factor (anti-VEGF), bevacizumab and ranibizumab, has revolutionized the treatment of neovascular age-related macular degeneration (nAMD).…”

“…The rAAV vectors are found to be the most effective in retinal gene therapy due to long-lasting photoreceptor transduction and RPE. [1] Delivery of various substances directly into the vitreous of the eye using viral vectors will certainly undergo dynamic development in the coming years. Another potentially effective method of AMD gene therapy may be treatment targeted at HIF transcription factors, i.e.…”

Induction of Heat Shock Protein 70 in Mouse RPE as an In Vivo Model of Transpupillary Thermal Stimulation

“…The pathogenesis of dry AMD is not yet fully understood, but during the progression of the disease, different multicomponent aggregates accumulate in the RPE environment [10]. High oxidative stress in the retina, RPE damage due to reactive oxygen species, disturbed autophagy, chronic inflammation, and malfunctioning of the complement system have been associated with dry AMD [11][12][13][14][15]. In addition, aged tissues generally have weakened ability to maintain proteostasis [5,16].…”