A nanopore membrane regulator device for laser modulated flow after glaucoma surgery.

Glaucoma, the second most common cause of blindness in the world, is a multifactorial disease with several risk factors, of which intraocular pressure (IOP) is a primary contributing factor. Filtration surgery is one of the most effective means to significantly lower IOP compared to medical or laser treatments, and it is typically reserved for advanced disease. However, there are high rates of postoperative complications associated with the procedure, often from over- or under-filtration. To address these problems, the glaucoma drainage device regulator (GDDR) implant was developed to allow post-operative control of aqueous flow and IOP. The device, a tube with a nanopore membrane, is placed beneath the scleral flap. Postoperatively, the membrane surface can be ruptured with a laser to augment flow through the system. This feature allows adjustable control of aqueous flow and diminishes the risk of hypotony in the early postoperative period.

Mutational Profile and Retinal Phenotypes of PCARE-Related Cone-Rod Dystrophies in a Mexican Cohort.

Purpose: The aim of the study is to describe the genotype and phenotype of a Mexican cohort with PCARE-related retinal disease. Methods: The study included 14 patients from 11 unrelated pedigrees with retinal dystrophies who were demonstrated to carry biallelic pathogenic variants in PCARE. Visual assessment methods included best corrected visual acuity, color fundus photography, Goldmann visual field test, kinetic perimetry, dark/light adapted chromatic perimetry, full-field electroretinography, autofluorescence imaging, and spectral domain-optical coherence tomography imaging. Genetic screening was performed either by gene panel sequencing or by exome sequencing. Results: According to the results of multimodal imaging and functional tests, all 14 patients were diagnosed with cone-rod dystrophy. Six different PCARE pathogenic alleles were identified in our cohort, including three novel mutations: c.3048_3049del (p.Tyr1016∗), c.3314_3315del (p.Ser1105∗), and c.551A > G (p.His184Arg). Notably, alleles p.His184Arg, p.Arg613∗, and p.Arg984∗ were present in 18 of the 22 (82%) PCARE alleles from probands in our cohort. Conclusion: Our work expands the PCARE mutational profile by identifying three novel pathogenic variants causing retinal dystrophy. While phenotypic variations occurred among patients, a cone-rod dystrophy pattern was observed in all affected individuals.

MicroRNAs as potential biomarkers and therapeutic targets in age-related macular degeneration.

Age-related macular degeneration (AMD) involves degenerative and neovascular alteration in the macular region of the retina resulting in central vision loss. AMD can be classified into dry (dAMD) and wet AMD (wAMD). There is no established treatment for dAMD, and therapies available for wAMD have limited success. Diagnosis in early AMD stages is difficult due to the absence of clinical symptoms. Currently, imaging tests are used in the diagnosis of AMD, but cannot predict the clinical course. The clinical limitations to establishing a diagnosis of AMD have led to exploration for innovative and more sensitive tests to support the diagnosis and prognosis of the disease. MicroRNAs (miRNAs) are small single-stranded non-coding RNA molecules that negatively regulate genes by post-transcriptional gene silencing. Because these molecules are dysregulated in various processes implicated in the pathogenesis of AMD, they could contribute to the early detection of the disease and monitoring of its progression. Studies of miRNA profiling have indicated several miRNAs as potential diagnostic biomarkers of AMD, but no approved biomarker is available at present for early AMD detection. Thus, understanding the function of miRNAs in AMD and their use as potential biomarkers may lead to future advances in diagnosis and treatment. Here we present a brief review of some of the miRNAs involved in regulating pathological processes associated with AMD and discuss several candidate miRNAs proposed as biomarkers or therapeutic targets for AMD.

Exogenous CFH Modulates Levels of Pro-Inflammatory Mediators to Prevent Oxidative Damage of Retinal Pigment Epithelial Cells with the At-Risk CFH Y402H Variant.

Age-related macular degeneration (AMD) is a complex, progressive degenerative retinal disease. Retinal pigment epithelial (RPE) cells play an important role in the immune defense of the eye and their dysfunction leads to the progressive irreversible degeneration of photoreceptors. Genetic factors, chronic inflammation, and oxidative stress have been implicated in AMD pathogenesis. Oxidative stress causes RPE injury, resulting in a chronic inflammatory response and cell death. The Y402H polymorphism in the complement factor H (CFH) protein is an important risk factor for AMD. However, the functional significance of CFH Y402H polymorphism remains unclear. In the present study, we investigated the role of CFH in the pro-inflammatory response using an in vitro model of oxidative stress in the RPE with the at-risk CFH Y402H variant. ARPE-19 cells with the at-risk CFH Y402H variant were highly susceptible to damage caused by oxidative stress, with increased levels of inflammatory mediators and pro-apoptotic factors that lead to cell death. Pretreatment of the ARPE-19 cell cultures with exogenous CFH prior to the induction of oxidative stress prevented damage and cell death. This protective effect may be related to the negative regulation of pro-inflammatory cytokines. CFH contributes to cell homeostasis and is required to modulate the pro-inflammatory cytokine response under oxidative stress in the ARPE-19 cells with the at-risk CFH Y402H variant.

Aldose Reductase Inhibition Prevents Development of Posterior Capsular Opacification in an In Vivo Model of Cataract Surgery.

Purpose: Cataract surgery is a procedure by which the lens fiber cell mass is removed from its capsular bag and replaced with a synthetic intraocular lens. Postoperatively, remnant lens epithelial cells can undergo an aberrant wound healing response characterized by an epithelial-to-mesenchymal transition (EMT), leading to posterior capsular opacification (PCO). Aldose reductase (AR) inhibition has been shown to decrease EMT markers in cell culture models. In this study, we aim to demonstrate that AR inhibition can attenuate induction of EMT markers in an in vivo model of cataract surgery. Methods: A modified extracapsular lens extraction (ECLE) was performed on C57BL/6 wildtype, AR overexpression (AR-Tg), and AR knockout mice. Immunofluorescent staining for the myofibroblast marker α-smooth muscle actin (α-SMA), epithelial marker E-cadherin, and lens fiber cell markers αA-crystallin and Aquaporin 0 was used to characterize postoperative PCO. Quantitative reverse transcription PCR (qRT-PCR) was employed to quantify postoperative changes in α-SMA, vimentin, fibronectin, and E-cadherin. In a separate experiment, the AR inhibitor Sorbinil was applied postoperatively and qRT-PCR was used to assess changes in EMT markers. Results: Genetic AR knockout reduced ECLE-induced upregulation of α-SMA and downregulation of E-cadherin. These immunofluorescent changes were mirrored quantitatively in changes in mRNA levels. Similarly, Sorbinil blocked characteristic postoperative EMT changes in AR-Tg mice. Interestingly, genetic AR knockout did not prevent postoperative induction of the lens fiber cell markers αA-crystallin and Aquaporin 0. Conclusions: AR inhibition prevents the postoperative changes in EMT markers characteristic of PCO yet preserves the postoperative induction of lens fiber cell markers.

The Transcription Factor Prdm16 Marks a Single Retinal Ganglion Cell Subtype in the Mouse Retina.

Purpose: Retinal ganglion cells (RGC) can be categorized into roughly 30 distinct subtypes. How these subtypes develop is poorly understood, in part because few unique subtype markers have been characterized. We tested whether the Prdm16 transcription factor is expressed by RGCs as a class or within particular ganglion cell subtypes. Methods: Embryonic and mature retinal sections and flatmount preparations were examined by immunohistochemistry for Prdm16 and several other cell type-specific markers. To visualize the morphology of Prdm16+ cells, we utilized Thy1-YFP-H transgenic mice, where a small random population of RGCs expresses yellow fluorescent protein (YFP) throughout the cytoplasm. Results: Prdm16 was expressed in the retina starting late in embryogenesis. Prdm16+ cells coexpressed the RGC marker Brn3a. These cells were arranged in an evenly spaced pattern and accounted for 2% of all ganglion cells. Prdm16+ cells coexpressed parvalbumin, but not calretinin, melanopsin, Smi32, or CART. This combination of marker expression and morphology data from Thy1-YFP-H mice suggested that the Prdm16+ cells represented a single ganglion cell subtype. Prdm16 also marked vascular endothelial cells and mural cells of retinal arterioles. Conclusions: A single subtype of ganglion cell appears to be uniquely marked by Prdm16 expression. While the precise identity of these ganglion cells is unclear, they most resemble the G9 subtype described by Völgyi and colleagues in 2009. Future studies are needed to determine the function of these ganglion cells and whether Prdm16 regulates their development.

Development of a laser controlled device to modulate intraocular pressure.

INTRODUCTION: The current standard of treatment for glaucoma is trabeculectomy. The use of glaucoma drainage devices has increased in recent years since its efficacy and safety was established as it provides an alternative surgical option. A downfall of these devices is the lack of proper flow rate control. Areas covered: In this paper we describe a glaucoma drainage device regulator that has already been protoyped and undergone initial testing. It consists of an implantable device with a semipermeable membrane that is used during glaucoma surgery and can be opened with either thermal or photodisruptive laser to adjust the amount of flow precisely and non-invasively, addressing the current difficulties of glaucoma surgeries. A literature search was conducted using MEDLINE and manuscript references for studies published in English between 2000 and 2015 using the terms glaucoma, trabeculectomy and glaucoma drainage devices. Expert commentary: The GDDR device can decrease surgical risk and allow surgeons to post-operatively adjust flow as clinically needed using a non-invasive method. Further testing is planned to substantiate these initial results and evaluate the device's biocompatibility, tunability and efficacy.