Efficacy of haptic sutured in-the-bag intraocular lens for intraocular lens-capsule complex stability: a comparison of three insertion methods.

AIM: To evaluate the efficacy and stability of haptic sutured in-the-bag intraocular lens (IOL) in eyes with zonular instability. METHODS: A total 60 eyes of 60 patients were included in this retrospective cohort study. Postoperative stability in three groups [haptic sutured IOL in the bag, IOL in the bag insertion with haptics oriented toward areas of zonulysis, IOL with capsular tension ring (CTR) in the bag insertion] were compared according to the IOL insertion methods. To evaluate the IOL stability, the changes of anterior chamber depth (ACD), refraction, contraction of anterior continuous curvilinear capsulotomy (CCC) area, and tilt of IOL were compared. RESULTS: There was no significant difference in change of ACD (-0.04±0.01 mm in group of haptic sutured IOL, -0.07±0.01 mm in group of CTR insertion) and refraction (0.05±0.05 D in group of haptic sutured IOL, 0.37±015 D in group of CTR insertion) between the group of haptic sutured IOL in the bag and CTR insertion group. But in comparison of CCC contraction and IOL tilt, CTR insertion group showed less contraction (1.00%±0.52%) and less IOL tilt (2.66°±0.11°) than the group of haptic sutured IOL in the bag (6.32%±1.36%, 3.47°±0.11°, respectively). The CTR insertion group showed the least CCC contraction and the least tilt. CONCLUSION: In eyes with zonular instability, the method of haptic sutured IOL in-the-bag shows comparable stability in ACD and refraction in comparison with IOL with CTR in the bag insertion. The method of IOL only in-the-bag insertion shows the largest contraction of CCC and the largest tilt of IOL.

COMP-Ang1: Therapeutic potential of an engineered Angiopoietin-1 variant.

The Angiopoietin-1/2 system is an opportune target for therapeutic intervention in a wide range of vascular pathologies, particularly through its association with endothelium. The complex multi-domain structure of native human Angiopoietin-1 has hindered its widespread applicability as a therapeutic agent, prompting the search for alternative approaches to mimicking the Ang1:Tie2 signalling axis; a system with highly complex patterns of regulation involving multiple structurally similar molecules. An engineered variant, Cartilage Oligomeric Matrix Protein - Angiopoietin-1 (COMP-Ang1), has been demonstrated to overcome the limitations of the native molecule and activate the Tie2 pathway with several fold greater potency than Ang1, both in vitro and in vivo. The therapeutic efficacy of COMP-Ang1, at both the vascular and systemic levels, is evident from multiple studies. Beneficial impacts on skeletal muscle regeneration, wound healing and angiogenesis have been reported alongside renoprotective, anti-hypertensive and anti-inflammatory effects. COMP-Ang1 has also demonstrated synergy with other compounds to heighten bone repair, has been leveraged for potential use as a co-therapeutic for enhanced targeted cancer treatment, and has received considerable attention as an anti-leakage agent for microvascular diseases like diabetic retinopathy. This review examines the vascular Angiopoietin:Tie2 signalling mechanism, evaluates the potential therapeutic merits of engineered COMP-Ang1 in both vascular and systemic contexts, and addresses the inherent translational challenges in moving this potential therapeutic from bench-to-bedside.

Start codon disruption with CRISPR/Cas9 prevents murine Fuchs' endothelial corneal dystrophy.

A missense mutation of collagen type VIII alpha 2 chain (COL8A2) gene leads to early-onset Fuchs' endothelial corneal dystrophy (FECD), which progressively impairs vision through the loss of corneal endothelial cells. We demonstrate that CRISPR/Cas9-based postnatal gene editing achieves structural and functional rescue in a mouse model of FECD. A single intraocular injection of an adenovirus encoding both the Cas9 gene and guide RNA (Ad-Cas9-Col8a2gRNA) efficiently knocked down mutant COL8A2 expression in corneal endothelial cells, prevented endothelial cell loss, and rescued corneal endothelium pumping function in adult Col8a2 mutant mice. There were no adverse sequelae on histology or electroretinography. Col8a2 start codon disruption represents a non-surgical strategy to prevent vision loss in early-onset FECD. As this demonstrates the ability of Ad-Cas9-gRNA to restore the phenotype in adult post-mitotic cells, this method may be widely applicable to adult-onset diseases, even in tissues affected with disorders of non-reproducing cells.

Systemic AAV10.COMP-Ang1 rescues renal glomeruli and pancreatic islets in type 2 diabetic mice.

INTRODUCTION: Diabetic hyperglycemia causes progressive and generalized damage to the microvasculature. In renal glomeruli, this results in the loss of podocytes with consequent loss of constitutive angiopoietin-1 (Ang1) signaling, which is required for stability of the glomerular endothelium. Repeated tail vein injection of adenovirus expressing COMP-Ang1 (a stable bioengineered form of Ang1) was previously reported to improve diabetic glomerular damage despite the liver and lungs being primary targets of adenoviral infection. We thus hypothesized that localizing delivery of sustained COMP-Ang1 to the kidney could increase its therapeutic efficacy and safety for the treatment of diabetes. RESEARCH DESIGN AND METHODS: Using AAVrh10 adeno-associated viral capsid with enhanced kidney tropism, we treated 10-week-old uninephrectomized db/db mice (a model of type 2 diabetes) with a single dose of AAVrh10.COMP-Ang1 delivered via the intracarotid artery, compared with untreated diabetic db/db control and non-diabetic db/m mice. RESULTS: Surprisingly, both glomerular and pancreatic capillaries expressed COMP-Ang1, compensating for diabetes-induced loss of tissue Ang1. Importantly, treatment with AAVrh10.COMP-Ang1 yielded a significant reduction of glycemia (blood glucose, 241±193 mg/dL vs 576±31 mg/dL; glycosylated hemoglobin, 7.2±1.5% vs 11.3±1.3%) and slowed the progression of albuminuria and glomerulosclerosis in db/db mice by 70% and 61%, respectively, compared with untreated diabetic db/db mice. Furthermore, COMP-Ang1 ameliorated diabetes-induced increases of NF-kBp65, nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase-2 (Nox2), p47phox and productions of myeloperoxidase, the inflammatory markers in both renal and pancreatic tissues, and improved beta-cell density in pancreatic islets. CONCLUSIONS: These results highlight the potential of localized Ang1 therapy for treatment of diabetic visceropathies and provide a mechanistic explanation for reported improvements in glucose control via Ang1/Tie2 signaling in the pancreas.

Intracorneal ring segments followed by toric pseudoaccomodating IOL for treatment of patients with corneal ectasia and cataract.

PURPOSE: Surgical management of keratoconus aims to improve corneal curvature, prevent progression of corneal ectasia, and manage refractive error. In older individuals with concurrent cataracts, management can be challenging due to topographic irregularity and difficult-to-interpret IOL calculations. We describe a sequential combination of two surgical techniques-intrastromal corneal ring segments (e.g. intacs) insertion and toric pseudoaccomodating lens implantation-to successfully manage concurrent keratoconus and cataracts. OBSERVATIONS: In this case series, we present three eyes with corneal ectasia in two cataractous patients successfully managed by (1) Intacs placement to normalize corneal contour/asymmetry and enable more regular keratometry measurements, followed by (2) correction of astigmatism and presbyopia by placement of toric pseudoaccommodating IOL (Trulign) after cataract extraction. CONCLUSIONS AND IMPORTANCE: This is the first description, to the authors' knowledge, of the use of intraocorneal ring segments + toric pseudoaccommodating intraocular lenses for the management of concurrent keratoconus, cataract, and presbyopia.

Topical Pergolide Enhance Corneal Nerve Regrowth Following Induced Corneal Abrasion.

Purpose: Neurotrophic keratopathy is a degenerative disease that may be improved by nerve growth factor (NGF). Our aim was to investigate the use of pergolide, a dopamine (D1 and D2) receptor agonist known to increase the synthesis and release of NGF for regeneration of damaged corneal nerve fibers. Methods: Pergolide function was evaluated by measuring axon length and NGF levels by enzyme-linked immunosorbent assay in cultured chicken dorsal root ganglion (DRG) cells with serial doses of pergolide (10, 25, 50, 150, and 300 µg/ml) and with different concentrations of a D1 antagonist. Pergolide function was further evaluated by cornea nerve fiber density and wound healing in a cornea scratch mouse model. Results: Pergolide increased DRG axon length significantly at a dose between 50 and 300 µg/ml. Different concentrations of D1 antagonist (12, 24, 48, and 96 µg/ml) inhibited DRG axon length growth with pergolide (300 µg/ml). Pergolide (50 µg/ml) upregulated NGF expression in DRG cells at both 24 hours and 48 hours. Pergolide improved cornea nerve fiber density at both 1 week and 2 weeks. Pergolide also improved cornea wound healing. Conclusions: We demonstrated that pergolide can act to promote an increase in NGF which promotes corneal nerve regeneration and would therefore improve corneal sensation and visual acuity in eyes with peripheral neurotrophic keratopathy.

Chronic Dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice.

Degeneration of the retinal pigmented epithelium (RPE) and aberrant blood vessel growth in the eye are advanced-stage processes in blinding diseases such as age-related macular degeneration (AMD), which affect hundreds of millions of people worldwide. Loss of the RNase DICER1, an essential factor in micro-RNA biogenesis, is implicated in RPE atrophy. However, the functional implications of DICER1 loss in choroidal and retinal neovascularization are unknown. Here, we report that two independent hypomorphic mouse strains, as well as a separate model of postnatal RPE-specific DICER1 ablation, all presented with spontaneous RPE degeneration and choroidal and retinal neovascularization. DICER1 hypomorphic mice lacking critical inflammasome components or the innate immune adaptor MyD88 developed less severe RPE atrophy and pathological neovascularization. DICER1 abundance was also reduced in retinas of the JR5558 mouse model of spontaneous choroidal neovascularization. Finally, adenoassociated vector-mediated gene delivery of a truncated DICER1 variant (OptiDicer) reduced spontaneous choroidal neovascularization in JR5558 mice. Collectively, these findings significantly expand the repertoire of DICER1 in preserving retinal homeostasis by preventing both RPE degeneration and pathological neovascularization.

COMP-Ang1 Stabilizes Hyperglycemic Disruption of Blood-Retinal Barrier Phenotype in Human Retinal Microvascular Endothelial Cells.

Purpose: Current treatments for diabetic retinopathy (DR) have considerable limitations, underpinning the need for new therapeutic options. In this article, the ability of an engineered angiopoietin-1 variant (COMP-Ang1) to ameliorate the injurious effects of hyperglycemia on barrier integrity in a human retinal microvascular endothelial cell (HRMvEC) model is comprehensively investigated. Methods: Confluent HRMvECs were treated (0-72 hours) with d-glucose (5 or 30 mM) in the absence and presence of COMP-Ang1 (10-200 ng/mL). l-glucose (30 mM) was used as osmotic control. Posttreatment, intact cell monolayers were monitored for permeability to FITC-dextran 40 kDa. Cells were also harvested for analysis of interendothelial junction targets by RT-qPCR and Western blotting. The impact of receptor tyrosine kinase Tie2 gene silencing on COMP-Ang1 efficacy was also evaluated. Results: Treatment with 30 mM d-glucose (but not l-glucose) demonstrated a time-dependent elevation in the mean rate of FITC-dextran diffusion across intact HRMvEC monolayers, in parallel with significant reductions in mRNA/protein levels of occludin, claudin-5, ZO-1, and VE-Cadherin. These effects were all attenuated by COMP-Ang1 in a concentration-dependent fashion, with 200 ng/mL recovering barrier function by ∼88%, and recovering reduced interendothelial junction protein levels by more than 50%. Finally, Tie2 knockdown by small interfering RNA silencing blocked the ability of COMP-Ang1 to mitigate against hyperglycemia-induced permeabilization of HRMvECs and depletion of junctional expression levels. Conclusions: In summary, this article presents a reproducible in vitro cell study that quantifies the concentration-dependent efficacy of COMP-Ang1 to mitigate the injurious effects of hyperglycemic challenge on HRMvEC barrier properties via Tie2-mediated signaling.

The value of nutritional supplements in treating Age-Related Macular Degeneration: a review of the literature.

PURPOSE: To describe and evaluate the value of nutritional supplements in the management of age-related macular degeneration (AMD) through a review of the current literature. METHODS: An extensive literature search was performed, and key research articles exploring AREDS and AREDS-2 formulations, genetics, omega fatty acids, calcium and folic acid in high-risk women were reviewed. PubMed and Web of Science databases were used for generating articles to review. RESULTS: The AREDS and AREDS-2 trials, while difficult to validate, show support for antioxidant supplementation in reducing AMD progression in Caucasian populations. While genetic guided personalized medicine has been studied mainly with complement factor H and age-related maculopathy susceptibility 2 risk alleles, the data have not been reproducible. Women at a higher risk of cardiovascular disease may benefit from antioxidant therapies in preventing AMD. Omega 3 fatty acid supplementation has been widely supported through observational studies; however, randomized controlled trials have not shown benefit in disease progression. Calcium exposure has been linked to increased mechanisms in cell death and may be detrimental to older individuals with AMD. CONCLUSION: The data regarding nutritional supplements in preventing AMD progression are inconclusive, and therefore recommendations should be based on risk factors and demographic data.

Intravitreal AAV2.COMP-Ang1 Attenuates Deep Capillary Plexus Expansion in the Aged Diabetic Mouse Retina.

Purpose: We determine whether intravitreal angiopoietin-1 combined with the short coiled-coil domain of cartilage oligomeric matrix protein by adeno-associated viral serotype 2 (AAV2.COMP-Ang1) delivery following the onset of vascular damage could rescue or repair damaged vascular beds and attenuate neuronal atrophy and dysfunction in the retinas of aged diabetic mice. Methods: AAV2.COMP-Ang1 was bilaterally injected into the vitreous of 6-month-old male Ins2Akita mice. Age-matched controls consisted of uninjected C57BL/6J and Ins2Akita males, and of Ins2Akita males injected with PBS or AAV2.REPORTER (AcGFP or LacZ). Retinal thickness and visual acuity were measured in vivo at baseline and at the 10.5-month endpoint. Ex vivo vascular parameters were measured from retinal flat mounts, and Western blot was used to detect protein expression. Results: All three Ins2Akita control groups showed significantly increased deep vascular density at 10.5 months compared to uninjected C57BL/6J retinas (as measured by vessel area, length, lacunarity, and number of junctions). In contrast, deep microvascular density of Ins2Akita retinas treated with AAV2.COMP-Ang1 was more similar to uninjected C57BL/6J retinas for all parameters. However, no significant improvement in retinal thinning or diabetic retinopathy-associated visual loss was found in treated diabetic retinas. Conclusions: Deep retinal microvasculature of diabetic Ins2Akita eyes shows late stage changes consistent with disorganized vascular proliferation. We show that intravitreally injected AAV2.COMP-Ang1 blocks this increase in deep microvascularity, even when administered subsequent to development of the first detectable vascular defects. However, improving vascular normalization did not attenuate neuroretinal degeneration or loss of visual acuity. Therefore, additional interventions are required to address neurodegenerative changes that are already underway.

Maxillary Zoster and Neurotrophic Keratitis following Trigeminal Block.

Herpes zoster ophthalmicus is commonly used to describe viral reactivation from the trigeminal ganglia with ocular involvement. The ophthalmic branch is the most commonly involved, whereas the maxillary and mandibular dermatomes are less commonly affected. Neurotrophic ulcer may occur secondary to intentional or inadvertent damage to the trigeminal nucleus, root, ganglion, or any segment of the ophthalmic branch of this cranial nerve. We report a case of reactivated maxillary herpes zoster combined with neurotrophic keratitis due to percutaneous 2nd and 3rd branch of trigeminal nerve block with alcohol to treat trigeminal neuralgia. A 57-year-old female came to the ophthalmology department complaining of decreased visual acuity and skin vesicle over the right lower lid and cheek. She had undergone right trigeminal nerve block for treatment of trigeminal neuralgia. Clinical examination revealed neurotrophic keratitis and maxillary herpes zoster. She was treated with oral and topical antivirals and vigorous lubrication with eye drops. Her neurotrophic keratitis showed a slow recovery. Although a few cases of herpes zoster following nerve block have been described, it would appear that a case of simultaneous maxillary herpes zoster and neurotrophic keratitis following trigeminal block has not yet been documented. It is possible that trigeminal nerve block may cause reactivation of latent virus and refractory neurotrophic keratitis.

Detection of microvascular retinal changes in type I diabetic mice with optical coherence tomography angiography.

Optical coherence tomography (OCT) angiography is a dye-free and non-invasive angiography which allows visualization of retinal and choroid vascular flow, enabling observation of highly permeable and three dimensional vasculature. Although OCT angiography is providing new insights in human retinal and choroidal diseases, a few studies have been reported in experimental mice. In this study, to determine the potential of OCT angiography in experimental mice, we sought to examine whether OCT angiography can detect vascular change in type I diabetic mice. To conduct age dependent analysis, 2 and 6 month old male type 1 diabetic Ins2Akita/+ and age matched C57BL/6J mice were used. OCT angiography was performed by Heidelberg Spectralis OCT Angiography Module with 30° lens + mouse adapter lens. We acquired the OCT angiography image from the peripheral nasal position. For analysis of OCT angiography images, OCT angiography positive area were used for vascular density. We analyzed vascular density from the retinal surface (inner limiting membrane) to 120 µm depth with 4 µm steps in order to correlate vascular density vs depth (N = 4 per group). Vascular density of both mouse strains demonstrated three different peaks. By comparing with the OCT image, the first peak (superficial), second peak (intermediate) and third peak (deep) were located in nerve fiber layer/ganglion cell layer, inner plexiform layer/inner nuclear layer and outer plexiform layer/outer nuclear layer, respectively. We calculated vascular density of these peaks separately. In C57BL/6J mice, the vascular density in all three layers do not show significant difference between 2- and 6-month-old. On the other hand, 6-month-old Ins2Akita/+ mice showed a significant decrease of the vascular density in all three layers compared to 2-month-old Ins2Akita/+ mice. Also, the vascular density of 6-month-old Ins2Akita/+ mice in the deep layer showed a significant decrease compared to 2- and 6-month-old C57BL/6J mice. Thus, OCT angiography successfully detects retinal vascular difference between type I diabetic mice and control mice, and age-dependent vasculature change in type I diabetic mice. The diabetic mice demonstrated reduced vascular density due to reduced density of flowing deep vessels. Importantly, we observed this difference without retinal blood leakage, hemorrhage or neovascularization. Our analysis (vascular density vs retinal depth) suggests that OCT angiography is useful for in vivo detection of retinal vasculature alteration in experimental mice.

Placenta-specific drug delivery by trophoblast-targeted nanoparticles in mice.

Rationale: The availability of therapeutics to treat pregnancy complications is severely lacking, mainly due to the risk of harm to the fetus. In placental malaria, Plasmodium falciparum-infected erythrocytes (IEs) accumulate in the placenta by adhering to chondroitin sulfate A (CSA) on the surfaces of trophoblasts. Based on this principle, we have developed a method for targeted delivery of payloads to the placenta using a synthetic placental CSA-binding peptide (plCSA-BP) derived from VAR2CSA, a CSA-binding protein expressed on IEs. Methods: A biotinylated plCSA-BP was used to examine the specificity of plCSA-BP binding to mouse and human placental tissue in tissue sections in vitro. Different nanoparticles, including plCSA-BP-conjugated nanoparticles loaded with indocyanine green (plCSA-INPs) or methotrexate (plCSA-MNPs), were administered intravenously to pregnant mice to test their efficiency at drug delivery to the placenta in vivo. The tissue distribution and localization of the plCSA-INPs were monitored in live animals using an IVIS imaging system. The effect of plCSA-MNPs on fetal and placental development and pregnancy outcome were examined using a small-animal high-frequency ultrasound (HFUS) imaging system, and the concentrations of methotrexate in fetal and placental tissues were measured using high-performance liquid chromatography (HPLC). Results: plCSA-BP binds specifically to trophoblasts and not to other cell types in the placenta or to CSA-expressing cells in other tissues. Moreover, we found that intravenously administered plCSA-INPs accumulate in the mouse placenta, and ex vivo analysis of the fetuses and placentas confirmed placenta-specific delivery of these nanoparticles. We also demonstrate successful delivery of methotrexate specifically to placental cells by plCSA-BP-conjugated nanoparticles, resulting in dramatic impairment of placental and fetal development. Importantly, plCSA-MNPs treatment had no apparent adverse effects on maternal tissues. Conclusion: These results demonstrate that plCSA-BP-guided nanoparticles could be used for the targeted delivery of payloads to the placenta and serve as a novel placenta-specific drug delivery option.

Epithelial Keratitis After Cataract Surgery.

PURPOSE: To evaluate the incidence, related perioperative factors, clinical characteristics, and possible etiologies of epithelial keratitis after cataract surgery. METHODS: A retrospective chart review of 666 eyes in 666 patients who underwent cataract surgery was performed to evaluate the incidence of epithelial keratitis and related factors in the postoperative period. RESULTS: Postoperative epithelial keratitis developed in 15 eyes. Eleven of the 15 eyes were diagnosed with herpes simplex keratitis (HSK); 10 of the 11 eyes were diagnosed by polymerase chain reaction, and the remaining 1 eye by clinical diagnosis. All patients diagnosed with HSK had no previous clinical history of the infection before undergoing cataract surgery. Initially, the diagnosis of all 15 eyes was toxic keratitis, but the final diagnosis of 11 of the initial 15 was found to be epithelial herpes keratitis. The incision location was shown to be related to the occurrence of HSK in our study (P < 0.05). CONCLUSIONS: HSK epithelial keratitis after cataract surgery is a relatively uncommon complication and can be misdiagnosed in its early disease course because of its relative rarity. This study explores the possibility that the temporal corneal penetrating incisional approach used in routine cataract surgery interrupts the corneal nerves and subsequently can trigger reactivation of HSK.

Pediatric keratoconus: a review of the literature.

PURPOSE: To describe the epidemiology and prevalence, rates of progression, difference between adult and pediatric populations, and therapeutic approaches to pediatric keratoconus from documented literature. METHODS: A literature search was done on PubMed using key words including pediatric keratoconus, children with keratoconus, adult keratoconus, penetrating keratoplasty, corneal cross-linking and intracorneal ring segments. The literature was reviewed and reported to explore the key epidemiological differences between the pediatric and adult population with regards to presentation and treatment options. RESULTS: Pediatric keratoconus is more aggressive than adult keratoconus, which has been explained by structural differences in the cornea between both populations. High rates of progression were documented in pediatric populations. While corneal collagen cross-linking, intracorneal ring segments and penetrating keratoplasties have been used as therapies in the pediatric population, the literature overwhelmingly shows higher rates of failure and progression despite these measures as compared to adults. CONCLUSION: Pediatric keratoconus is more aggressive than adult keratoconus, and current therapies used in adults may not be sufficient for the pediatric population.