A Phase I, Single Ascending Dose Study of GEM103 (Recombinant Human Complement Factor H) in Patients with Geographic Atrophy.

Purpose: To establish the safety, tolerability, pharmacokinetics, and pharmacodynamics of an intravitreal injection of recombinant human complement factor H (CFH), GEM103, in individuals with genetically defined age-related macular degeneration (AMD) and geographic atrophy (GA). Design: Phase I single ascending-dose, open-label clinical trial (ClinicalTrials.gov identifier, NCT04246866). Participants: Twelve individuals 50 years of age or older with a confirmed diagnosis of foveal GA in the study eye. Methods: Participants were assigned to the increasing dose cohorts and received 1 50-µl intravitreal injection of GEM103 at doses of 50 µg/eye, 100 µg/eye, 250 µg/eye, or 500 µg/eye; dose escalation was dependent on the occurrence of dose-limiting toxicities. Main Outcome Measures: Safety assessments included ocular and systemic adverse events (AEs), ocular examinations, clinical laboratory and vital signs, and serum antidrug antibody levels. Biomarkers, measured in the aqueous humor (AH), included CFH and complement activation biomarkers factor Ba and complement component 3a. Results: No dose-limiting toxicities were reported, enabling escalation to the maximum study dose. No anti-GEM103 antidrug antibodies were detected during the study. Four participants experienced AEs; these were nonserious, mild or moderate in severity, and unrelated to GEM103. The AEs in 2 of these participants were related to the intravitreal injection procedure. No clinically significant ophthalmic changes and no ocular inflammation were observed. Visual acuity was maintained and stable throughout the 8-week follow-up period. No choroidal neovascularization occurred. CFH levels increased in a dose-dependent manner after GEM103 administration with supraphysiological levels observed at week 1; levels were more than baseline for 8 weeks or more in all participants receiving single doses of 100 µg or more. Complement activation biomarkers were reduced 7 days after dose administration. Conclusions: A single intravitreal administration of GEM103 (up to 500 µg/eye) was well tolerated in individuals with GA. Of the few mild or moderate AEs reported, none were determined to be related to GEM103. No intraocular inflammation or choroidal neovascularization developed. CFH levels in AH were increased and stable for 8 weeks, with pharmacodynamic data suggesting that GEM103 restored complement regulation. These results support further development in a repeat-dose trial in patients with GA with AMD.

Evaluation of Port Delivery System with ranibizumab for the treatment of neovascular age-related macular degeneration.

Current treatment of neovascular age-related macular degeneration involves periodic intravitreal injections of anti-VEGF medication, creating a burden to patients and physicians, resulting in nonadherence to recommended dosing schedules. The Port Delivery System with ranibizumab offers a long-term solution that involves implantation of a device into the pars plana and provides continuous release of anti-VEGF medication into the vitreous, thus requiring fewer office visits. The Port Delivery System has demonstrated comparable visual and anatomic outcomes to monthly injections and shows promise in alleviating the patient burden in the treatment of neovascular age-related macular degeneration, making possible better long-term real-world visual outcomes.

Understanding seizure risk with wide field fundus photography: Implications for screening guidelines in the era of COVID-19 and telemedicine.

PURPOSE: To report two cases of photosensitive seizures due to fundus photography flash. OBSERVATIONS: Two patients with seizure history present to a retina clinic for routine follow up. While obtaining imaging, these patients experienced a seizure triggered by fundus camera flash. CONCLUSIONS: Fundus photography is essential and ubiquitous amongst optometry and ophthalmology practices, especially in the rising era of telemedicine in the setting of the recent COVID-19 pandemic. To our knowledge, there are no other reports in the literature of seizures triggered by fundus photography flash. However, we believe this to be an under-reported phenomenon and suggest that all eye care providers screen patients for a history of seizures or epilepsy prior to fundus photography.

Acute Vision Loss.

Acute vision loss can be transient (lasting <24 hours) or persistent (lasting >24 hours). When patients present with acute vision loss, it is important to ascertain the duration of vision loss and whether it is a unilateral process affecting one eye or a bilateral process affecting both eyes. This article focuses on causes of acute vision loss in the nontraumatic setting and provides management pearls to help health care providers better triage these patients.

Baseline choroidal thickness as a predictor for response to anti-vascular endothelial growth factor therapy in diabetic macular edema.

PURPOSE: To determine the association between baseline subfoveal choroidal thickness and short-term response to intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy in diabetic macular edema (DME). DESIGN: Retrospective, consecutive case series. METHODS: Fifty-three eyes from 42 patients diagnosed with treatment-naïve DME were treated with 3 monthly intravitreal injections of ranibizumab or bevacizumab. Serial enhanced depth imaging optical coherence tomography scans were used to measure subfoveal choroidal thickness and central macular thickness (CMT). Anatomic response (CMT decrease ≥ 50 µm) and functional response (best-corrected visual acuity gain ≥ 1 line) were assessed at 3 months follow-up using univariate and multivariate analyses. RESULTS: After 3 monthly anti-VEGF treatments, subfoveal choroidal thickness decreased significantly (225 µm at baseline, 201 µm at 3 months, P < .0001). The anatomic responder group (32 eyes) had a greater baseline choroidal thickness (243 ± 15 µm) than the nonresponder group (21 eyes, 198 ± 13 µm, P = .03). Similarly, the functional responder group (28 eyes) tended to have a greater baseline subfoveal choroidal thickness (239 ± 12 µm) than the nonresponder group (25 eyes, 211 ± 16 µm, P = .08). Multivariate analyses revealed that a greater baseline subfoveal choroidal thickness was associated with a better anatomic (odds ratio = 1.12 for every 10 µm increase, P = .03) and functional response (odds ratio = 8.45 for >200 µm vs ≤ 200 µm, P = .008). CONCLUSION: Baseline subfoveal choroidal thickness may help predict which patients with DME will respond more favorably in the short term to intravitreal anti-VEGF pharmacotherapy. In this study, eyes with a thicker baseline subfoveal choroidal thickness had better short-term anatomic and functional responses.

Retinoschisis and hyperopia associated with partial monosomy of 6q and partial trisomy of 11q.

BACKGROUND: Retinoschisis, or retinal lamellar splitting, can occur in a number of hereditary conditions. The most common cause of congenital or childhood onset retinoschisis is the clinical entity known as juvenile retinoschsis, which is caused by mutations in the X-linked retinoschisis 1 gene. Genes other than X-linked retinoschisis 1 gene have rarely been implicated in association with hereditary retinoschisis. METHODS: We describe a 9-year-old male who presented with several phenotypic features associated with partial monosomy of chromosome 6q and partial trisomy of chromosome 11q, including myelomeningocele, mental and growth retardation, seizures, microcephaly, scoliosis, and facial dysmorphisms, as well as novel ocular findings including bilateral retinoschisis and hyperopia. RESULTS: This case report highlights the necessity for a detailed ophthalmic examination of patients with both 6q deletions as well as 11q duplications to ensure accurate and timely diagnosis and treatment of the complications associated with the described ocular conditions.

alpha4 Integrin/FN-CS1 mediated leukocyte adhesion to brain microvascular endothelial cells under flow conditions.

Insights into sequential leukocyte-endothelial interactions during leukocyte trafficking have been obtained through experiments using human umbilical vein endothelial cells (HUVEC) under flow conditions. To investigate leukocyte-brain endothelial cell interactions, we developed a dynamic in vitro system, using Transfected Human Brain Microvascular Endothelial Cells (THBMEC) and a parallel plate flow chamber. Human peripheral blood mononuclear cells (PBMC) were perfused across confluent THBMEC cultures at a velocity that approximates the rate found in human brain capillaries. Leukocyte-THBMEC interactions were visualized by phase-contrast microscopy, and images were captured on a CCD camera. To simulate inflammatory conditions, we activated THBMEC with the inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma), which up-regulated chemokine and adhesion molecule expression in THBMEC without affecting the distribution of immunoreactivity for tight junction-associated proteins. PBMC adhesion was enhanced by cytokine-mediated activation of THBMEC. G protein-coupled receptor (GPCR) activation was essential for leukocyte-THBMEC interaction, as pertussis toxin (PTX) treatment of PBMC abrogated PBMC adhesion to activated THBMEC. The anti-alpha4 integrin antibody, natalizumab, infused into MS patients, significantly reduced the adhesion of their ex vivo PBMC to activated THBMEC under flow conditions. Further study showed that alternatively spliced fibronectin containing the CS1 region (FN-CS1), but not Vascular Cell Adhesion Molecule type 1 (VCAM-1), was the ligand of alpha4 integrin on activated THBMEC. Blocking FN-CS1 abrogated PBMC adhesion on activated THBMEC, while anti-VCAM-1 antibodies had no effect. These results established a novel in vitro dynamic BBB model. We also demonstrated the dependence of leukocyte-endothelial interactions in this model on alpha4 integrins and FN-CS1.