Retinitis pigmentosa is an untreatable, inherited retinal disease that leads to blindness. The disease initiates with the loss of night vision due to rod photoreceptor degeneration, followed by irreversible, progressive loss of cone photoreceptor 1-3. Cone loss is responsible for the main visual handicap, as cones are essential for day and high-acuity vision 4. Their loss is indirect, as most genes associated with retinitis pigmentosa are not expressed by these cells. We previously showed that factors secreted from rods are essential for cone viability 5-8. Here we identified one such trophic factor by expression cloning and named it rod-derived cone viability factor (RdCVF). RdCVF is a truncated thioredoxin-like protein specifically expressed by photoreceptors. The identification of this protein offers new treatment possibilities for retinitis pigmentosa. We used a viability assay based on cone-enriched primary cultures from chicken embryos 9 for expression cloning. Unlike those of mammals, bird retinas are cone-dominated. Cones represent 60-80% of the total population in cultured cells 8. Once cultured, these cells degenerate over a few days, but adding conditioned medium from wild-type mouse retinal explants delays this loss 8. We carried out a screen to isolate factors that could support cone survival. We constructed a cDNA expression library from neural retinas of 5-week-old wild-type mice and we purified plasmid DNA from pools of 100 individual clones and used them to transfect COS-1 cells. We added conditioned medium from transfected COS cells to chicken retinal cultures seeded in 96-well plates. After 7 d of culture, we carried out an automated viability assay and we screened 2,100 pools, corresponding to 210,000 individual clones. Pool 939 contained twice as many living cells as the negative controls (Fig. 1). We isolated clone 939.09.08 by limiting dilution and found that it contained a 502-bp insert with an open reading frame encoding a putative polypeptide of 109 amino acids. We named this protein rod-derived cone viability factor (RdCVF, international patent no. PCT/EP 02/03810; Supplementary Fig. 1 online).
Purpose There is an urgent need to address how to best provide ophthalmic care for patients with retinal disease receiving intravitreal injections with anti-vascular endothelial growth factor agents during the ongoing global COVID-19 pandemic. This article provides guidance for ophthalmologists on how to deliver the best possible care for patients while minimizing the risk of infection. Methods The Vision Academy's Steering Committee of international retinal disease experts convened to discuss key considerations for managing patients with retinal disease during the COVID-19 pandemic. After reviewing the existing literature on the issue, members put forward recommendations that were systematically refined and voted on to develop this guidance. Results The considerations focus on the implementation of steps to minimize the exposure of patients and healthcare staff to COVID-19. These include the use of personal protective equipment, adherence to scrupulous hygiene and disinfection protocols, pre-screening to identify symptomatic patients, and reducing the number of people in waiting rooms. Other important measures include triaging of patients to identify those at the greatest risk of irreversible vision loss and prioritization of treatment visits over monitoring visits where possible. In order to limit patient exposure, ophthalmologists should refrain from using treatment regimens that require frequent monitoring. Conclusion Management of patients with retinal disease receiving intravitreal injections during the COVID-19 pandemic will require adjustment to regular clinical practice to minimize the risk of exposure of patients and healthcare staff, and to prioritize those with the greatest medical need. The safety of patients and healthcare staff should be of paramount importance in all decision-making.
Five vascular endothelial growth factor receptor (VEGFR) ligands (VEGF-A, -B, –C, -D, and placental growth factor [PlGF]) constitute the VEGF family. VEGF-A binds VEGF receptors 1 and 2 (VEGFR1/2), whereas VEGF-B and PlGF only bind VEGFR1. Although much research has been conducted on VEGFR2 to elucidate its key role in retinal diseases, recent efforts have shown the importance and involvement of VEGFR1 and its family of ligands in angiogenesis, vascular permeability, and microinflammatory cascades within the retina. Expression of VEGFR1 depends on the microenvironment, is differentially regulated under hypoxic and inflammatory conditions, and it has been detected in retinal and choroidal endothelial cells, pericytes, retinal and choroidal mononuclear phagocytes (including microglia), Müller cells, photoreceptor cells, and the retinal pigment epithelium. Whilst the VEGF-A decoy function of VEGFR1 is well established, consequences of its direct signaling are less clear. VEGFR1 activation can affect vascular permeability and induce macrophage and microglia production of proinflammatory and proangiogenic mediators. However the ability of the VEGFR1 ligands (VEGF-A, PlGF, and VEGF-B) to compete against each other for receptor binding and to heterodimerize complicates our understanding of the relative contribution of VEGFR1 signaling alone toward the pathologic processes seen in diabetic retinopathy, retinal vascular occlusions, retinopathy of prematurity, and age-related macular degeneration. Clinically, anti-VEGF drugs have proven transformational in these pathologies and their impact on modulation of VEGFR1 signaling is still an opportunity-rich field for further research.
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