Phase 1 Study of JNJ-81201887 Gene Therapy in Geographic Atrophy Secondary to Age-related Macular Degeneration.

OBJECTIVE: To evaluate the safety and tolerability of a single intravitreal injection of JNJ-81201887 (JNJ-1887) in patients with geographic atrophy (GA) secondary to advanced dry age-related macular degeneration (AMD). DESIGN: Phase 1, open-label, single-center, first-in-human clinical study. SUBJECTS: Adult patients (aged ≥50 years) with GA secondary to AMD in the study-treated eye (treated eye) with a best corrected visual acuity (BCVA) Snellen equivalent of 20/200 or worse in the treated eye (20/80 or worse after the first 3 patients), a total GA lesion size between 5 and 20 mm2 (2-8 disc area), and BCVA of 20/800 or better in fellow, non-treated eye were included. METHODS: Patients (N=17) were sequentially enrolled into low (3.56×1010 viral genome [vg]/eye; n=3), intermediate (1.07×1011 vg/eye; n=3), and high (3.56×1011 vg/eye; n=11) dose cohorts without steroid prophylaxis and assessed for safety and tolerability over 24 months. MAIN OUTCOME MEASURES: Safety and tolerability outcomes included assessment of ocular and non-ocular treatment-emergent adverse events (AEs) over 24 months. Secondary outcomes included GA lesion size and growth rate. RESULTS: Baseline patient characteristics were consistent with the disease under study, and all enrolled patients had foveal center-involved GA. JNJ-1887 was well tolerated across all cohorts, with no dose-limiting AEs. There were no serious or systemic AEs related to study intervention. Overall, 5/17 (29%) patients experienced 6 events of mild ocular inflammation related to study treatment; exam findings in all resolved, and AEs resolved in 4 of 5 patients following topical steroids or observation. One unresolved vitritis event, managed with observation, occurred in a patient with an unrelated fatal AE. No endophthalmitis or new-onset choroidal neovascularization was reported. GA lesion growth rate was similar among all cohorts over 24 months. For treated eyes in the high-dose cohort, GA lesion growth rate showed continued decline through 24 months, with a reduction in mean square root lesion growth from 0.211 mm at months 0-6 to 0.056 mm at months 18-24. CONCLUSIONS: All 3 studied doses of JNJ-1887 had a manageable safety profile through 24 months of follow-up. Further investigation of JNJ-1887 for the treatment of GA is warranted.

Genetics of Diabetic Retinopathy.

PURPOSE OF REVIEW: The goal of this paper is to review the latest findings in understanding the genetics of diabetic retinopathy. We highlight recent literature using a variety of molecular genetic techniques to identify variants which contribute to genetic susceptibility for diabetic retinopathy. RECENT FINDINGS: New genome-wide association study (GWAS) and whole-exome sequencing approaches have been utilized to identify both common and rare variants associated with diabetic retinopathy. While variants have been identified in isolated studies, no variants have been replicated across multiple studies. The identification of genetic factors associated with diabetic retinopathy remains elusive. This is due to the multifactorial nature of the disease, small sample sizes for GWAS, and difficulty in controlling covariates of the disease. Larger populations as well as utilization of new sequencing and data analysis techniques may lead to new insights into genetic factors associated with diabetic retinopathy in the future.

RESOLUTION, DEPTH OF FIELD, AND PHYSICIAN SATISFACTION DURING DIGITALLY ASSISTED VITREORETINAL SURGERY.

PURPOSE: To evaluate depth of field, lateral resolution, and image quality of a heads-up 3D visualization system for vitreoretinal surgery using physician survey and optical measurement outcomes. METHODS: Depth of field and lateral resolution were compared between the standard ocular viewing system and the digital 3D system at ×5, ×13, and ×18 magnification by 6 retinal surgeons. Optical techniques were used as well as a survey of surgeon impression. Surgeon impression surveys were performed after 6 weeks of surgical use of the device. RESULTS: Physician questionnaire survey scores for depth of field at high magnification were better for the digital 3D system and equivalent for all other categories. Measured lateral resolution was 36.7 mm and 16.6 mm at ×5 magnification (P < 0.001), 14.3 mm and 6.4 mm at ×13 magnification (P < 0.001), and 9.8 mm and 4.2 mm (P < 0.001) at ×18 magnification for the digital 3D and oculars, respectively. Measured depth of field was 4.00 mm and 6.78 mm at ×5 magnification (P = 0.027), 0.72 mm and 0.86 mm at ×13 (P = 0.311), and 0.28 mm and 0.40 mm at ×18 magnification (P = 0.235) for the oculars and digital 3D, respectively. CONCLUSION: Lateral resolution of the digital 3D system was half that of the ocular viewing system and there was some improvement in depth of field with the digital system. Surgeon impression suggested that the digital system was superior when evaluating depth of field at high magnification.

Long-Chain Polyunsaturated Fatty Acids and Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is one of the leading causes of blindness worldwide. Long-chain and very long-chain polyunsaturated fatty acids (LC and VLC-PUFAs) have been linked to AMD pathogenesis through epidemiologic, biochemical, and genetic studies; however, the exact mechanisms of pathogenesis are unknown. Here, we review the scientific and clinical evidence supporting the role of PUFAs in AMD and discuss future directions for elucidating the roles of these fatty acids in AMD pathogenesis.

Emerging Concepts for RNA Therapeutics for Inherited Retinal Disease.

Inherited retinal diseases (IRD) encompass a wide spectrum of hereditary blindness with significant genetic heterogeneity. Therapeutics regulating gene expression on an RNA level have significant promise for treating IRD. In this review, we review the molecular basis of oligonucleotide therapeutics such as ribozymes, RNA interference (RNAi), antisense oligonucleotides (ASO), CRISPRi/a, and their applications to treatments of IRD.

Peripapillary serous detachment in multiple evanescent white dot syndrome.

BACKGROUND: To report the presence of transient peripapillary serous detachments in multiple evanescent white dot syndrome. METHODS: Retrospective case series. RESULTS: Four eyes of four patients diagnosed with multiple evanescent white dot syndrome presented with peripapillary serous detachments. Diagnosis was based on clinical presentation, fundus findings, and angiographic findings. All 4 were female with age ranges between 24 and 40 years and presented with photopsias, an enlarged scotoma contiguous with the blind spot, and chorioretinal white dots in the posterior pole with characteristic angiographic features. All of the serous detachments resolved or were greatly reduced concomitantly with the resolution of the patient's other clinical symptoms and fundus findings. CONCLUSION: The authors report peripapillary serous detachments as a previously unreported manifestation of multiple evanescent white dot syndrome. These seem to be self limited with concurrent resolution with the rest of the patient's symptoms.

A molecular revolution in uveal melanoma: implications for patient care and targeted therapy.

Uveal melanoma is the most common primary intraocular malignancy and has a strong propensity for fatal metastasis. Recent advances in the molecular genetics of uveal melanoma are revolutionizing our understanding of this cancer and the care of patients. The development of a new molecular classification of uveal melanoma based on a widely available 15-gene expression profile now allows patients at high risk of metastasis to be identified early so that individualized management can be offered. The recent discovery of major driver mutations in uveal melanoma provide a rational basis for development of new targeted therapies. Taken together, these advances are transforming our understanding and management of uveal melanoma with the ultimate goal of improving patient outcomes.

Transient cell-cell interactions in neural circuit formation.

The wiring of the nervous system requires a complex orchestration of developmental events. Emerging evidence suggests that transient cell-cell interactions often serve as positional cues for axon guidance and synaptogenesis during the assembly of neural circuits. In contrast to the relatively stable cellular interactions between synaptic partners in mature circuits, these transient interactions involve cells that are not destined to be pre- or postsynaptic cells. Here we review the roles of these transient cell-cell interactions in a variety of developmental contexts and describe the mechanisms through which they organize neural connections.

Bioequivalence and the food effect of macitentan/tadalafil 10/20 fixed-dose combination tablets versus the use of single-component tablets in healthy subjects.

The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed-dose combination (FDC) of macitentan/tadalafil in a single tablet and the free combination of both drugs, and to evaluate the food effect on the 10/20 mg FDC in healthy participants. In this single-center, randomized, open-label, 3-way crossover, single-dose Phase 1 study in healthy adult participants, macitentan/tadalafil was administered as a 10/20 mg FDC formulation and compared with the free combination of macitentan and tadalafil. The food effect on the FDC was also evaluated. Pharmacokinetic sampling (216 h) was conducted. The 90% confidence intervals (CIs) for the geometric mean ratios of maximum observed plasma analyte concentration (Cmax) and area under the plasma analyte concentration-time curves (AUCs) for Treatment A (FDC, fasted) versus C (free combination, fasted) were within bioequivalence limits demonstrating that the FDC formulation can be considered bioequivalent to the free combination. The 90% CIs for the geometric mean ratios of Cmax and AUC for Treatment B (FDC, fed) versus A (FDC, fasted) were contained within bioequivalence limits demonstrating that there was no food effect. The administration of the 10/20 mg FDC was generally safe and well tolerated in healthy participants. This study demonstrated bioequivalence between the FDC of macitentan/tadalafil (10/20 mg) in a single tablet and the free combination of both drugs in healthy participants, and that the FDC can be taken without regard to food, similarly to the individual components. The FDC was generally safe and well tolerated.

Characterization of a clinician-scientist cohort in ophthalmology: a demographic analysis of k grant awardees in ophthalmology.

OBJECTIVE: To analyze ophthalmologists who are National Institutes of Health (NIH) K grant awardees to characterize clinician-scientists in ophthalmology. DESIGN: Cohort study. PARTICIPANTS: Ophthalmologists who have received a K award from 1996 through 2010. METHODS: K08 and K23 grant awardees were identified through the NIH Research Portfolio Online Reporter database. Information including gender, institution, educational degrees, and success in obtaining an R01 grant was analyzed. MAIN OUTCOME MEASURES: Receipt of an R01 grant. RESULTS: One hundred five ophthalmologists were identified who received K08 or K23 grants from the National Eye Institute from 1996 through 2010. Overall, 75% of these were male, although 43% of K awardees were women from 2006 through 2010. Sixty-five percent (68/105) of individuals came from ophthalmology departments that ranked in the top 20 of NIH funding in 2010. The most predominant subspecialties represented were retina (32%), cornea (22%), and glaucoma (15%). Among the K awardees, 40% (42/105) had a doctor of philosophy (PhD) degree in addition to their medical doctor degree. From 1996 through 2000, 61% (23/38) were successful in obtaining an R01 grant, whereas only 13% (5/39) from 2001 through 2005 obtained R01 grants (P<0.001). CONCLUSIONS: Gender disparities exist among K awardees in ophthalmology, but these seem to be improving over time. None of the other variables studied-gender, PhD degree, specialty, or funding tier-was associated with obtaining R01 funding. This study helps to characterize the clinician-scientist cohort in ophthalmology and to identify areas to improve the recruitment of these individuals. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

SGLT2 Inhibitor-Induced Low-Grade Ketonemia Ameliorates Retinal Hypoxia in Diabetic Retinopathy-A Novel Hypothesis.

Diabetic retinopathy (DR) is a well-recognized microvascular complication of diabetes. Growing evidence suggests that, in addition to retinal vascular damage, there is significant damage to retinal neural tissue in DR. Studies reveal neuronal damage before clinically evident vascular lesions and DR is now classified as a neurovascular complication. Hyperglycemia causes retinal damage through complex metabolic pathways leading to oxidative stress, inflammation, vascular damage, capillary ischemia, and retinal tissue hypoxia. Retinal hypoxia is further worsened by high oxygen consumption in the rods. Persistent hypoxia results in increases in vascular endothelial growth factor (VEGF) and other pro-angiogenic factors leading to proliferative DR/macular edema and progressive visual impairment. Optimal glucose control has favorable effects in DR. Other treatments for DR include laser photocoagulation, which improves retinal oxygenation by destroying the high oxygen consuming rods and their replacement by low oxygen consuming glial tissue. Hypoxia is a potent stimulator of VEGF, and intravitreal anti-VEGF antibodies are effective in regressing macular edema and in some studies, retinal neovascularization. In this review, we highlight the complex pathophysiology of DR with a focus on retinal oxygen/fuel consumption and hypoxic damage to retinal neurons. We discuss potential mechanisms through which sodium-glucose cotransporter 2 (SGLT2) inhibitors improve retinal hypoxia-through ketone bodies, which are energetically as efficient as glucose and yield more ATP per molecule of oxygen consumed than fat, with less oxidative stress. Retinal benefits would occur through improved fuel energetics, less hypoxia and through the anti-inflammatory/oxidative stress effects of ketone bodies. Well-designed studies are needed to explore this hypothesis.

Advances in Retinal Oximetry.

Similar to other organs, the retina relies on tightly regulated perfusion and oxygenation. Previous studies have demonstrated that retinal blood flow is affected in a variety of eye and systemic diseases, including diabetic retinopathy, age-related macular degeneration, and glaucoma. Although measurement of peripheral oxygen saturation has become a standard clinical measurement through the development of pulse oximetry, developing a noninvasive technique to measure retinal oxygen saturation has proven challenging, and retinal oximetry technology currently remains inadequate for reliable clinical use. Here, we review current strategies and approaches, as well as several newer technologies in development, and discuss the future of retinal oximetry.

Implementing the new normal in ophthalmology care beyond COVID-19.

The COVID-19 pandemic has altered the clinical landscape immeasurably. The need to physical distance requires rethinking how we deliver ophthalmic care. Within healthcare, we will need to focus our resources on the five T's: Utilising technology, multidisciplinary clinical teams with wide professional talents need to work efficiently to reduce patient contact time. With regular testing, this will allow us to reduce the risk further. We also must acknowledge the explosion of different modalities to train our future ophthalmologists and the global challenges and advantages that these bring. Finally, we must not forget the psychological impact that this pandemic will have on ophthalmologists and ancillary staff, and need to have robust mechanisms for support.

Research Funding, Income, and Career Satisfaction Among Clinician-Scientists in Ophthalmology in the United States.

PURPOSE: The purpose of this study was to characterize clinician-scientists in ophthalmology and identify factors associated with successful research funding, income, and career satisfaction. DESIGN: Cross-sectional study. METHODS: A survey was conducted of clinician-scientists in ophthalmology at US academic institutions between April 17, 2019, and May 19, 2019. Collected information including 1) demographic data; 2) amount, type, and source of startup funding; first extramural grant; and first R01-equivalent independent grant; 3) starting and current salaries; and 4) Likert-scale measurements of career satisfaction were analyzed using multivariate regression. RESULTS: Ninety-eight clinician-scientists in ophthalmology were surveyed across different ages (mean: 48 ± 11 years), research categories, institutional types, geographic regions, and academic ranks. Median startup funding ranged from $50-99k, and median starting salaries ranged from $150-199k. A majority of investigators (67%) received their first extramural award from the National Eye Institute, mainly through K-award mechanisms (82%). The median time to receiving their first independent grant was 8 years, mainly through an R01 award (70%). Greater institutional startup support (P = .027) and earlier extramural grant success (P = .022) were associated with earlier independent funding. Male investigators (P = .001) and MD degreed participants (P = .008) were associated with higher current salaries but not starting salaries. Overall career satisfaction increased with career duration (P = .011) but not with earlier independent funding (P = .746) or higher income (P = .300). CONCLUSIONS: Success in research funding by clinician-scientists in ophthalmology may be linked to institutional support and earlier acquisition of extramural grants but does not impact academic salaries. Nevertheless, career satisfaction among clinician-scientists improves with time, which is not necessarily influenced by research or financial success.

Cooling Anesthesia for Intravitreal Injection: Results of the Prospective Open-Label, Dose-Ranging COOL-1 Trial.

PURPOSE: To evaluate the safety and efficacy of a novel medical device to provide cooling anesthesia to the eye as local anesthesia for intravitreal injections. STUDY DESIGN: First in human, open-label study of 43 subjects assessed at three different doses: -10°C for 20 seconds (group 1), -15°C for 15 seconds (group 2), and -15°C for 20 seconds (group 3). Main outcome measures were safety and pain of injection using a numeric rating scale (NRS). RESULTS: Cooling anesthesia did not result in any serious ocular adverse events. One grade 1 adverse event was a vasovagal response during cooling administration which resolved immediately after cooling. Mean NRS scores at the time of injection for each group ranged from 2.5 to 4.3 There was a statistically significant difference between pain scores of the 3 groups at injection in aggregate but not in pairwise comparisons (P value = 0.047). There was a statistically significant decrease in pain from injection to 5 minutes post injection in all groups (P value = 0.00008, 0.003, 0.0005 for groups 1, 2, 3, respectively) as well as from 5 minutes to 24-48 hours (P value = 0.00001, 0.018, and 0.0545 for groups 1, 2, 3, respectively). CONCLUSION: The rapid cooling anesthesia device was well tolerated for achieving local anesthesia among patients receiving intravitreal injections with no serious ocular adverse events.

BILATERAL ENTEROCOCCUS FAECALIS ENDOPHTHALMITIS WITH MULTIPLE RECURRENCES.

PURPOSE: To describe the first case report of a bilateral recurrent Enterococcus faecalis endophthalmitis postcataract surgery. METHODS: Case report with a description of the timeline, diagnosis, and management of a patient with bilateral recurrent E. faecalis endophthalmitis. RESULTS: An 89-year-old man presented 6 weeks' postcataract surgery with pain, tearing, and blurred vision in the left eye. B-scan ultrasonography revealed vitritis and cultures postvitrectomy grew E. faecalis. There was gradual improvement in vision postintravitreal vancomycin administration. Four years later, the patient experienced another episode of E. faecalis endophthalmitis in the right eye postcataract extraction, followed by several additional episodes in both eyes posttreatment. CONCLUSION: Enterococcus faecalis is a rare but highly virulent cause of endophthalmitis that may remain sequestered in the capsular bag, despite aggressive treatment. Even after recurrent episodes, early vitrectomy and aggressive antibiotic therapy may prove to be effective in preventing vision loss.

Assessment of Respiratory Droplet Transmission During the Ophthalmic Slit-Lamp Exam: A Particle Tracking Analysis.

PURPOSE: The global COVID-19 pandemic has resulted in a renewed focus on the importance of personal protective equipment (PPE) and other interventions to decrease spread of infectious diseases. Although several ophthalmology organizations have released guidance on appropriate PPE for surgical procedures and ophthalmology clinics, there is limited experimental evidence that demonstrates the efficacy of various interventions that have been suggested. In this study, we evaluated high-risk aspects of the slit-lamp exam and the effect of various PPE interventions, specifically the use of a surgical mask and a slit-lamp shield. DESIGN: Experimental simulation study. METHODS: This was a single-center study in a patient simulation population. This study examined the presence of particles in the air near or on a slit-lamp, a simulated slit-lamp examiner, or a simulated patient using a fluorescent surrogate of respiratory droplets. RESULTS: Simulated coughing without a mask or slit-lamp shield resulted in widespread dispersion of fluorescent droplets during the model slit-lamp examination. Coughing with a mask resulted in the most significant decrease in droplets; however, particles still escaped from the top of the mask. Coughing with the slit-lamp shield alone blocked most of forward particle dispersion; however, significant distributions of respiratory droplets were found on the slit-lamp joystick and table. Coughing with both a mask and slit-lamp shield resulted in the least dispersion to the simulated examiner and the simulated patient. Scanning electron microscopy demonstrated particle sizes of 3-100 µm. CONCLUSIONS: Masking had the greatest effect in limiting spread of respiratory droplets, whereas slit-lamp shields and gloves also contributed to limiting exposure to droplets from SARS-CoV-2 during slit-lamp examination.

ELOVL2: Not just a biomarker of aging.

DNA methylation of the ELOVL2 (Elongation Of Very Long Chain Fatty Acids-Like 2) promoter is one of the most robust molecular biomarkers for chronological age, but whether ELOVL2 plays a functional role in aging has not been explored. ELOVL2 encodes a transmembrane protein involved in the synthesis of very long polyunsaturated fatty acids (VLC-PUFAs). These fatty acids play important roles in retinal biology and photoreceptor renewal, key processes implicated in age-related eye diseases such as age-related macular degeneration (AMD). Here, we summarize our work deciphering the role of ELOVL2 in the eye emphasizing the potential functional role of age-related DNA methylation in the pathophysiology of AMD.