Bispecific VEGF-A and Angiopoietin-2 Antagonist RO-101 Preclinical Efficacy in Model of Neovascular Eye Disease.

Objective: To investigate preclinical data regarding the efficacy and biocompatibility of a bispecific protein, RO-101, with effects on VEGF-A and angiopoietin-2 (Ang-2) for use in retinal diseases. Design: Experimental study. Subjects: Brown Norway rats and New Zealand White Cross rabbits. Methods: Preclinical study data of RO-101 in terms of target-specific enzyme-linked immunosorbent assay binding affinity to VEGF-A and Ang-2, vitreous half-life, inhibition of target-receptor interaction, laser choroidal neovascular membrane animal model, human umbilical vein endothelial cell migration, and biocompatibility was obtained. Where applicable, study data were compared with other anti-VEGF agents. Main Outcome Measures: Binding affinity, half-life, biocompatibility, and efficacy of RO-101. Neovascularization prevention by RO-101. Results: RO-101 demonstrated a strong binding affinity for VEGF-A and Ang-2 and in vitro was able to inhibit binding to the receptor with higher affinity than faricimab. The half-life of RO-101 is comparable to or longer than current VEGF inhibitors used in retinal disease. RO-101 was found to be biocompatible with retinal tissue in Brown Norway rats. RO-101 was as effective or more effective than current anti-VEGF therapeutics in causing regression of neovascular growth in vivo. Conclusions: RO-101 is a promising candidate for use in retinal diseases. In preclinical models, RO-101 demonstrated similar or higher regression of neovascular growth to current anti-VEGF therapeutics with comparable or longer half-life. It also demonstrates a strong binding affinity for VEGF-A and Ang-2. It also was shown to be biocompatible with retinal tissue in animal studies, indicating potential compatibility for use in humans. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

EFFICACY OF INTRAVITREAL AFLIBERCEPT INJECTIONS IN THE TREATMENT OF IDIOPATHIC RETINAL VASCULITIS, ANEURYSMS, AND NEURORETINITIS SYNDROME.

PURPOSE: To present a case of idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome that was successfully managed with serial intravitreal aflibercept injections. METHODS: Ophthalmic imaging and visual acuity were used to monitor disease state and track treatment methods to determine the most valuable combination of treatment medication and treatment interval. RESULTS: A 28-year-old woman with idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome status after panretinal photocoagulation of both eyes presented with bilateral cystoid macular edema. We demonstrate successful management of retinal cystoid macular edema associated with idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome using serial intravitreal aflibercept injections. CONCLUSION: Intravitreal aflibercept has a useful role in managing the potential retinal complications associated with idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome and provides further insights into treatment of the later stages of this rare disease.

Bioceramic implant reduces intraocular VEGF levels.

Elevated intraocular levels of angiogenic cytokines such as vascular endothelial growth factor (VEGF) have been implicated the development of diabetic retinopathy. Over a decade of clinical evidence shows intravitreal injection of anti-VEGF agents is associated with decreased disease progression and preservation of vision. However, the treatment burden associated with monthly injections limits the effectiveness of existing anti-VEGF therapies. Current research has focused on sustained treatment paradigms such as longer acting drugs, drug delivery implants, and gene therapy. In this study, we tested a novel approach by dialyzing proteins from the vitreous using bioceramic implant composed of hydroxyapatite. Preliminary in vitro and in vivo studies demonstrate a high affinity and capacity for VEGF absorption. After three months implantation in New Zealand White Cross rabbits, the hydroxyapatite demonstrated good biocompatibility with no inflammation and normal retinal physiology and histology. These studies demonstrate that prolonged VEGF suppression intraocularly may be accomplished with a bioceramic implant.

Vitreous protein binding with nanopore dialysis membrane device.

Age-related macular degeneration (AMD) is one of the leading causes of blindness in the industrialized world, affecting over 8 million patients in the United State alone. While the wet (exudative) form of the disease is treated with intraocular injections, there are currently no approved therapies available for the dry (non-exudative) form of the disease which often affects both eyes in patients with AMD. Current research has focused on developing drugs that can be injected into the eye, but the treatment burden associated with monthly injections limits the effectiveness of this approach. Hence, there is a pressing need for a long-term therapeutic solution for patients suffering from this blinding disease. We detail a novel implantable intraocular device, which adsorbs and traps complement factors associated with AMD. In this study, we tested a novel approach by dialyzing proteins from the vitreous using biocompatible implants composed of a nanopore polyacrylonitrile polymer membrane. Preliminary in vitro and in vivo studies demonstrate a high affinity and capacity for complement protein absorption. After a three-month implantation in New Zealand White Cross rabbits, the implant demonstrated good biocompatibility with no inflammation and normal retinal physiology and histology. These studies demonstrate that prolonged CF suppression intraocularly may be accomplished with a nanopore polymer membrane.

COLORADO AGE-RELATED MACULAR DEGENERATION REGISTRY: Design and Clinical Risk Factors of the Cohort.

PURPOSE: To study new and existing risk factors related to age-related macular degeneration (AMD) phenotypes in a Colorado cohort. METHODS: Age-related macular degeneration was categorized into early, intermediate, or advanced forms. Controls (n = 180) were patients with cataract and no AMD. Demographic and clinical data were gathered by patient interview and verified by chart review. Image data were reviewed by vitreoretinal specialists. Statistical analysis included univariable and multivariate logistic regression analysis (P < 0.05). RESULTS: Among the 456 patients with AMD, 157 (34.4%), 80 (17.6%), and 219 (48.0%) had the early/intermediate, geographic atrophy, and neovascular forms of the disease, respectively. Adjusted for age, African-American race was associated with a reduced risk of early/intermediate (adjusted odds ratio [AOR] = 0.08, confidence interval [CI] = 0.01-0.67) and neovascular AMD (AOR = 0.15, CI = 0.03-0.72). A family history of AMD was a risk factor for early/intermediate (AOR = 4.08, CI = 2.30-7.25), geographic atrophy (AOR = 8.62, CI = 3.77-19.7), and neovascular AMD (AOR = 3.76, CI = 2.16-6.56). A history of asthma was related to the early/intermediate form of AMD (AOR = 2.34, CI = 1.22-4.46). CONCLUSION: Studying AMD in specific populations may reveal novel risk factors such as our finding of a relationship between asthma history and AMD.

INCREASED COMPLEMENT LEVELS IN HUMAN VITREOUS ASPIRATES OF PROLIFERATIVE DIABETIC RETINOPATHY AND RETINAL DETACHMENT EYES.

PURPOSE: To evaluate levels of complement factors in human vitreous of eyes with retinal detachments (RDs) and proliferative diabetic retinopathy (PDR) eyes. METHODS: Human vitreous samples were collected from eyes undergoing routine vitrectomy at the University of Colorado Health Eye Center (Aurora, CO). Complement factor D, component C5/C5a, and component C9 levels were measured using enzyme-linked immunosorbent assay and multiplex assays. Retinal detachment and PDR eyes were compared with controls, which were defined as eyes with macular holes or epiretinal membranes. RESULTS: The levels of complement factor D in PDR (mean = 2,110.0 ng/mL, P = 0.001) and RD (mean = 660.9 ng/mL, P = 0.03) eyes were statistically significantly higher than controls (mean = 290.5 ng/mL). The levels of complement component C9 were also more elevated in PDR (P = 0.004) compared with control but not in RD eyes. CONCLUSION: Elevated complement factors, particularly of the alternative pathway, were noted in PDR and RD eyes compared with controls. One potential explanation for this is that the oxidative stress in RD and PDR eyes leads to complement dysregulation and alternative complement upregulation.

Metabolomics Analysis of Human Vitreous in Diabetic Retinopathy and Rhegmatogenous Retinal Detachment.

The vitreous humor is a highly aqueous eye fluid interfacing with the retina and lens and providing shape. Its molecular composition provides a readout for the eye's physiological status. Changes in cellular metabolism underlie vitreoretinal pathologies, but despite routine surgical collection of vitreous, only limited reports of metabolism in the vitreous of human patients have been described. Vitreous samples from patients with rhegmatogenous retinal detachment ( n = 25) and proliferative diabetic retinopathy ( n = 9) were profiled along with control human vitreous samples ( n = 8) by untargeted mass-spectrometry-based metabolomics. Profound changes were observed in diabetic retinopathy vitreous, including altered glucose metabolism and activation of the pentose phosphate pathway, which provides reducing equivalents to counter oxidative stress. In addition, purine metabolism was altered in diabetic retinopathy, with decreased xanthine and elevated levels of related purines (inosine, hypoxanthine, urate, allantoate) generated in oxidant-producing reactions. In contrast, the vitreous metabolite profiles of retinal detachment patients were similar to controls. In total, our results suggest a rewiring of vitreous metabolism in diabetic retinopathy that underlies disease features such as oxidative stress and furthermore illustrates how the vitreous metabolic profile may be impacted by disease.

Real-time measurement of needle forces and acute pressure changes during intravitreal injections.

BACKGROUND: The purpose of this study was to use a physiological pressure transducer to measure real-time, continuous pressure changes in an ex vivo study model of porcine eyes to record the amount of force needed for scleral penetration and to measure acute intraocular pressure rise during intravitreal injections. METHODS: A pressure transducer was inserted into the anterior chamber of 30 fresh porcine eyes, and intraocular pressure was measured 2 s prior to intravitreal injection until 2 s after. A force transducer plate was used to insert various gauge needles into the vitreous cavity and the amount of force in Newtons (N) required for scleral penetration was recorded. RESULTS: For scleral perforation, 32- and 30-gauge needles required 0.44 N and 0.45 N, significantly less than larger gauge needles (P < 0.05). Similarly, 27- and 25-gauge needles required more force than smaller gauge needles but less than 19 gauge (P < 0.05). Intraocular pressure increased an average of 64.5 mmHg during intravitreal injection. Two seconds postinjection intraocular pressure readings showed a residual intraocular pressure increase of 11.1 mmHg from pre-injection baseline. CONCLUSION: Real-time continuous recordings of pressure reveal that an instantaneous intraocular pressure spike occurs during intravitreal injection and appears to be separate from the intraocular pressure spike that occurs during needle insertion. This pressure spike is transient and has not been captured by previous methods of intraocular pressure measurement, which rely on single time point measurements. The clinical significance of this brief intraocular pressure spike is unclear and warrants further investigation.

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.

CONCURRENT ENDOPHTHALMITIS AND ANTERIOR SEGMENT ISCHEMIA AFTER STRABISMUS SURGERY.

BACKGROUND/PURPOSE: To report a case of simultaneous endophthalmitis and anterior segment ischemia (ASI) that occurred in a patient after strabismus surgery. This is the first known case of both complications occurring at the same time. METHODS: Case report. RESULTS: A 60-year-old woman presented with eye pain and loss of vision 6 days after uncomplicated strabismus surgery for thyroid eye disease. On examination, she had corneal edema, anterior segment fibrin, an atonic iris, and no view to the posterior segment. On fluorescein angiography of the anterior segment, a large portion of the iris was nonperfused. Posterior segment ultrasound showed dense vitritis and a choroidal abscess. Intraoperative cultures grew methicillin-resistant Staphylococcus aureus. CONCLUSIONS: Endophthalmitis and anterior segment ischemia are both exceedingly rare complications of strabismus surgery. It is possible that each one occurred independently, but more likely one process potentiated the other. One possible mechanism is inflammation-induced thrombosis.

VITRECTOMY TO REMOVE POSTERIORLY RETAINED IRIS EXPANSION RING.

PURPOSE: To describe management of posteriorly retained iris expansion ring-a newly reported complication of phacoemulsification surgery in a patient with intact posterior capsule. METHODS: Case report. PATIENTS: A 64-year-old monocular patient with history of regressed proliferative diabetic retinopathy after pars plana vitrectomy, long-standing glaucoma, and cataract, undergoing phacoemulsification for cataract removal, complicated by posterior migration of the Malyugin ring through area of zonular dehiscence despite intact posterior capsule, which resulted in significant visual disturbance. RESULTS: The intravitreal Malyugin ring was successfully removed by performing a standard 3-port 25-gauge vitrectomy and retrieving the mobilized ring into the barrel of the original injector device. CONCLUSION: A posteriorly retained iris expansion ring can be effectively extracted from the vitreous cavity with the original injector device, which allows for maximal control of the ring and minimal associated surgical trauma.

The influence of needle gauge and infection source on vitreous aspirate cultures.

BACKGROUND/AIMS: While the Endophthalmitis Vitrectomy Study (EVS) included only post-cataract surgery patients, the methods and data from that study are widely applied in the management of endophthalmitis of all types. We sought to examine how our experience with in-office vitreous aspiration differed from the EVS in two ways: first, by reviewing microbiological culture yields from vitreous aspirates obtained using 30-gauge needles versus 25-27-gauge needles and second, by reviewing culture yields in cases of endogenous versus non-endogenous endophthalmitis. METHODS: Cases of endophthalmitis over a 14-year period were reviewed when vitreous tap was the initial diagnostic procedure. The data included infection source, needle size used to obtain a vitreous aspirate, organism cultured and rates of unsuccessful attempts at vitreous aspiration or dry taps. RESULTS: 10 cases were endogenous endophthalmitis, while 36 cases were a mix of postoperative, post-traumatic, post-intravitreal injection and miscellaneous patients. A positive microbiological culture was obtained in 11/36 (31%) of vitreous taps using a 25-27-gauge needle and in 8/10 (80%) taps using a 30-gauge needle (p<0.01). A positive vitreous culture was obtained in 18/36 (50%) of all non-endogenous cases, while a positive result was obtained in 0/10 (0%) cases of endogenous endophthalmitis (p<0.01). CONCLUSIONS: The use of a smaller needle in obtaining vitreous samples in endophthalmitis did not lower the microbiological yield. A positive microbiological yield was significantly less likely in cases of endogenous endophthalmitis compared with non-endogenous cases. Vitreous tap as a method for identifying the causative organism in endogenous endophthalmitis was of limited utility.

Enhanced High-Density Line Spectral-Domain Optical Coherence Tomography Imaging of the Vitreoretinal Interface: Description of Selected Cases.

PURPOSE: We introduce a new method to observe the morphologic features of the vitreous with spectral-domain optical coherence tomography (SD-OCT) by evaluating and describing the posterior vitreous structure of various selected cases using enhanced high-density (HD) line mode. METHODS: This is a descriptive case series of SD-OCT images with enhanced HD line at Denver Health Medical Center, University of Colorado School of Medicine, in 2014. The medical records with ocular images for these patients were analyzed. RESULTS: Enhanced HD line in vitreoretinal mode with SD-OCT offered wide images with well-visible vitreoretinal interface. The posterior precortical vitreous pocket (PPVP), often mistaken as a posterior vitreous detachment on standard retina-based cross line mode, was easily identified. Vitreomacular adhesion and traction, absence or presence of connecting channels between PPVP and Cloquet's canal, liquefied vitreous lacuna, and emulsified silicone oil droplet-layer could be observed. CONCLUSIONS: SD-OCT using enhanced HD line in vitreoretinal mode enables clear visualization of the posterior vitreous structure and often reclassifies patients previously thought to have a posterior vitreous detachment.

Progression of gyrate atrophy measured with ultra-wide-field imaging.

The study aims to determine the progression of gyrate atrophy by measuring the area growth of chorioretinal atrophic lesions using ultra-wide-field images (UWFI). A retrospective, observational, and comparative study was conducted and UWFI (200°) were obtained from two patients with gyrate atrophy at baseline and follow-up. Measurements of atrophy were obtained for three types of lesions: Solitary atrophic lesions (SAL), De novo solitary lesions (DNSL), and peripapillary atrophy (PPA). Comparison of baseline and follow-up was done using t tests. Two patients with gyrate atrophy were included. Patient 1 presented 16 SAL, 5 DNSL, and PPA measured for both eyes (BE). Overall area growth (OAG) for SAL (expressed in decimals) presented a mean of 3.41, σ 3.07. DNSL area for BE presented a mean of 1586.08 P (2), σ 1069.55. OAG for PPA presented a mean of 1.21, σ 0.17. Patient 2 presented 5 SAL, no DNSL, and PPA was measured for BE. OAG for SAL presented a mean of 1.58, σ 1.05 (range 1.02-3.47). OAG for PPA presented a mean of 1.05, σ 0.001. Gyrate atrophy progression can be determined by measuring the changes in area using UWFI.

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.

Difference in ocular surface temperature by infrared thermography in phakic and pseudophakic patients.

PURPOSE: To assess the change in ocular surface temperature between healthy phakic and pseudophakic patients. METHODS: We included patients with no history of ocular disease other than cataract. Patients were divided into three groups: clear lens, cataract, and pseudophakic. All patients had two ocular surface digital thermal scans. An average of five surface points was used as the mean ocular surface temperature. Results were analyzed with a one-way analysis of variance and a Tukey's least significance difference test. The patients were further divided into phakic and pseudophakic groups. Correlation coefficients between several variables were done in order to assess dependencies. RESULTS: Fifty-six eyes (28 cataracts, 12 clear lenses, 16 pseudophakic) were enrolled. The mean ocular surface temperature in the cataract group was 34.14°C±1.51°C; clear lens: 34.43°C±2.27°C; and pseudophakic: 34.97°C±1.57°C. There were no statistical differences among the study groups (P=0.3). There was a nonsignificant negative correlation trend between age and surface temperature in the phakic group. The trend inverted in the pseudophakic group but without statistical significance. CONCLUSION: Although cataract extraction and intraocular lens implantation seem to induce a mild increase in ocular surface temperature, the effect is not clear and not significant.