Editorial: Novel Therapeutic Target and Drug Development in Neurovascular Retinal Diseases

Abstract

Editorial on the Research Topic Novel Therapeutic Target and Drug Development in Neurovascular Retinal Diseases Pathological ocular angiogenesis leads to blindness in retinopathy of prematurity (ROP), diabetic retinopathy (DR), and age-related macular degeneration (AMD). Clinically approved anti-VEGF therapy has limited effectiveness and side effect profile unfit for some patients (Bressler et al., 2012; Jalali et al., 2013; Klufas and Chan, 2015; Zhao and Singh, 2018; Bakri et al., 2019). Therefore, further understanding of the disease pathogenesis and exploration of new therapeutics are required. In this research topic, we highlighted new drug targets, therapeutic approaches, and technologies for treatment of ocular neovascularization. Understanding the interaction of endothelial cells with the surrounding cells is essential for the development of effective and safe therapeutics (Wilson and Sapieha, 2016; Binet et al., 2020; Fu et al., 2020). Neuronal metabolism regulates retinal vascular function (Joyal et al., 2018; Fu et al., 2019). In this research topic, Fouda et al. provided a systematic overview of the arginase pathway in acute retina and brain injury, and discussed the possibility of modulating this pathway to treat ischemia-induced neurodegeneration. Shetty and Corson summarized the vulnerability of endothelial cells to mitochondrial heme loss, and proposed that targeting intracellular heme via inhibiting heme synthesis or blocking heme transport may be a novel strategy to decrease retinal neovascularization. Further exploration of neural-vascular metabolism and interaction is needed. Endothelial cells utilize glucose, fatty acid and glutamine as substrates for energy and biomass for cell homeostasis and growth (Falkenberg et al., 2019). On the other hand, photoreceptors require glucose and fatty acids for energy production and function (Joyal et al., 2016). Therefore, when considering interventions for metabolic modulation, it is necessary to take into account the overall impact on various retinal cell types. In addition, the interaction of metabolic pathways in retinopathies also requires further investigation. Recently, low serine with increase in deoxysphingolipids is reported to correlate with macular disease (Gantner et al., 2019). Wang et al. revealed significant metabolic disturbances (such as amino acids and ketone bodies) in aqueous humor of patients with Posner-Schlossman syndrome that were identified with metabolomics. Further exploration of retinal metabolic interactions between amino acid, lipid pathways, and others would definitely attract great interests. Inflammation and autophagy are induced in response to stressed conditions such as in retinal metabolic disorders (Tang and Kern, 2011; Mitter et al., 2012; Kauppinen et al., 2016). Wang et al. discussed that persistent neuroinflammation exacerbates ocular neovascularization. They further explored the potential involvement of SOCS3 and c-Fos in the disease pathogenesis of retinopathies. Zhu et al. demonstrated that rapamycin induced autophagy and preserved trabecular meshwork cells in glucocorticoid-induced glaucoma mice can be a potential therapeutic approach to glaucoma. Recently, genomic analysis, transcriptome profiling, and proteomics have been used as a hypothesis free approach to identify drug targets in retinal neovascular diseases (Vahatupa et al., 2018; Desjarlais et al., 2019). Desjarlais et al. reported the discovery of down regulation of MicroRNA-96 in oxygen induced retinopathy (OIR) rats through next generation sequencing (NGS) screening. In vitro study demonstrated that overexpression of MicroRNA-96 stimulated tubulogenesis and migration against hyperoxia-induced endothelial dysfunction, while antagonizing microRNA-96 led to angiogenic impairment. Intravitreally supplementing microRNA-96 mimic preserved retinal/choroidal microvessels in the hyperoxic state of rat OIR model. Cheng et al. analyzed and compared transcriptome profiles in retinal-choroid tissues derived from donor patients with AMD and healthy controls. They identified that EFEMP1 gene was upregulated in the AMD, especially wet-AMD patients. Elevation of EFEMP1 product, fibulin-3, was confirmed in the serum of wet-AMD patients. In vitro overexpression and knockdown of EFEMP1 in human umbilical vein endothelial cells (HUVECs) confirmed the proangiogenic effect of this gene. Vähätupa et al. reviewed the elevation of crystallins, small heat shock proteins, during early hypoxic state of OIR as well as an increase of actomyosin complex and Filamin A-R-Ras axis at the peak of neovascularization that were discovered through proteomic analysis using sequential window acquisition of all theoretical mass spectra (SWATH-MS). Some crystallins are neuroprotective while others play a prominent role in the pathology of neovascularization. The actomyosin complex and Filamin A-R-Ras axis regulates vascular permeability of the angiogenic blood vessels. These proteomic changes were also confirmed patients with proliferative diabetic retinopathy (PDR) and retinal vein occlusion (RVO). RNA based therapeutic approaches against retinal neovascular disease have gained significant interest in recent years. Ma et al. found that silencing Trpc6 with RNA interference (RNAi) abolished high glucose-induced decreases in glutamate uptake and Müller glial cell death in vitro, suggesting that TRPC6 may be a promising target that deserves further investigation in animal models. Protection of neurovascular supporting cells Müller glia and regulation of Müller gliosis may protect against diabetic retinopathy (Coughlin et al., 2017; Le, 2017). Additionally, Guan et al. reported that MicroRNA-18a-5p is increased during neovascularization of OIR mice retina, adding to the list of miRNAs that is involved in this process (Zhou et al., 2016; Xia et al., 2018)....