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

PURPOSE: 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. PARTICIPANTS: Adult patients (≥50 years of age) with GA secondary to AMD in the study-treated eye (treated eye) with Snellen best-corrected visual acuity 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 best-corrected visual acuity of 20/800 or better in fellow, nontreated eye were included. METHODS: Patients (n = 17) were enrolled sequentially into low-dose (3.56 × 1010 viral genome/eye; n = 3), intermediate-dose (1.07 × 1011 viral genome/eye; n = 3), and high-dose (3.56 × 1011 viral genome/eye; n = 11) 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 nonocular 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 demonstrated foveal center-involved GA. JNJ-81201887 was well-tolerated across all cohorts, with no dose-limiting AEs. No serious or systemic AEs related to study intervention occurred. Overall, 5 of 17 patients (29%) experienced 5 events of mild ocular inflammation related to study treatment; examination findings in all resolved, and AEs resolved in 4 of 5 patients after 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. Geographic atrophy 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 through 6 to 0.056 mm at months 18 through 24. CONCLUSIONS: All 3 studied doses of JNJ-1887 showed a manageable safety profile through 24 months of follow-up. Further investigation of JNJ-1887 for the treatment of GA is warranted. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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.

COMPARISON OF RETINAL PATHOLOGY VISUALIZATION IN MULTISPECTRAL SCANNING LASER IMAGING.

PURPOSE: To compare retinal pathology visualization in multispectral scanning laser ophthalmoscope imaging between the Spectralis and Optos devices. METHODS: This retrospective cross-sectional study included 42 eyes from 30 patients with age-related macular degeneration (19 eyes), diabetic retinopathy (10 eyes), and epiretinal membrane (13 eyes). All patients underwent retinal imaging with a color fundus camera (broad-spectrum white light), the Spectralis HRA-2 system (3-color monochromatic lasers), and the Optos P200 system (2-color monochromatic lasers). The Optos image was cropped to a similar size as the Spectralis image. Seven masked graders marked retinal pathologies in each image within a 5 × 5 grid that included the macula. RESULTS: The average area with detected retinal pathology in all eyes was larger in the Spectralis images compared with Optos images (32.4% larger, P < 0.0001), mainly because of better visualization of epiretinal membrane and retinal hemorrhage. The average detection rate of age-related macular degeneration and diabetic retinopathy pathologies was similar across the three modalities, whereas epiretinal membrane detection rate was significantly higher in the Spectralis images. CONCLUSION: Spectralis tricolor multispectral scanning laser ophthalmoscope imaging had higher rate of pathology detection primarily because of better epiretinal membrane and retinal hemorrhage visualization compared with Optos bicolor multispectral scanning laser ophthalmoscope imaging.

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.

Nonisolated Small Bowel Gastrointestinal Angiodysplasias are Associated With Higher Rebleeding Rates When Compared With Isolated Small Bowel Gastrointestinal Angiodysplasia on Video Capsule Endoscopy.

BACKGROUND: Gastrointestinal angiodysplasias (GIAD) are commonly diagnosed in the small bowel but can be located in other areas of the gastrointestinal tract. About half of patients diagnosed with GIAD have more than 1 lesion and 20% of patients have GIAD in both the small bowel and a source outside of the small bowel (nonisolated to small bowel GIAD or NISGIAD). The remaining patients with GIAD have lesions isolated to the small bowel (ISGIAD). Complications including rebleeding, hospitalization and mortality rates have not been previously analyzed between these 2 groups. AIM: To compare rebleeding, hospitalization and mortality rates between ISGIAD and NISGIAD. The secondary goals were to evaluate comorbidities that may be associated with ISGIAD and/or NISGIAD, and to determine if any of these comorbidities are associated with a higher risk of rebleeding from GIAD. MATERIALS AND METHODS: This was a retrospective study that included 425 patients who underwent video capsule endoscopy between 2006 and 2013. Patients underwent esophagogastroduodenoscopy and colonoscopy before video capsule endoscopy. The primary indications for workup included obscure gastrointestinal bleeding. After exclusion criteria, 87 patients diagnosed with GIAD remained, 57 patients with ISGIAD and 30 with NISGIAD. Categorical variables were compared by the Fisher exact test or χ test and continuous data were compared using the Student T test. RESULTS: Risk factors associated with rebleeding rates included coronary artery disease, chronic kidney disease, and congestive heart failure on multivariate analysis. Odds ratios for rebleeding was found in patients with NISGIAD (odds ratio, 4.222; P=0.036). There was no difference in hospitalization rates between patients with ISGIAD and NISGIAD. There was no statistically significant difference in mortality from any cause at 30, 60, and 90 days in patients with ISGIAD and NISGIAD. CONCLUSIONS: In this retrospective analysis of GIAD at a single institution, patients with NISGIAD compared with ISGIAD had a 4 times odds of rebleeding within 1 year after capsule endoscopy. This is a novel study, as the distribution of GIAD has not been previously described as being a risk factor for rebleeding.

From minutes to years: predicting organotrifluoroborate solvolysis rates.

Organotrifluoroborates solvolyze in water at rates that vary over five orders of magnitude. The negative logarithm of the solvolytic rate constant, pk(B-F), correlates exceptionally well with the pKa of the analogous carboxylic acid (R(2) = 0.984). This unforeseen correlation may be of predictive value for several applications including Suzuki-Miyaura cross-coupling reactions and the design of (18)F-organotrifluoroborate radioprosthetic groups.

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.

Clinical Pharmacology Perspective on Development of Adeno-Associated Virus Vector-Based Retina Gene Therapy.

Adeno-associated virus (AAV) vector-based gene therapy is an innovative modality being increasingly investigated to treat diseases by modifying or replacing defective genes or expressing therapeutic entities. With its unique anatomic and physiological characteristics, the eye constitutes a very attractive target for gene therapy. Specifically, the ocular space is easily accessible and is generally considered "immune-privileged" with a low risk of systemic side effects following local drug administration. As retina cells have limited cellular turnover, a one-time gene delivery has the potential to provide long-term transgene expression. Despite the initial success with voretigene neparvovec (Luxturna), the first approved retina gene therapy, there are still challenges to be overcome for successful clinical development of these products and scientific questions to be answered. The current review paper aims to integrate published experience learned thus far for AAV-based retina gene therapy related to preclinical to clinical translation; first-in-human dose selection; relevant bioanalytical assays and strategies; clinical development considerations including trial design, biodistribution and vector shedding, immunogenicity, transgene expression, and pediatric populations; opportunities for model-informed drug development; and regulatory perspectives. The information presented herein is intended to serve as a guide to inform the clinical development strategy for retina gene therapy with a focus on clinical pharmacology.

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.

Pediatric orbital cellulitis: Case report of an unusual etiology and pathogen.

Orbital cellulitis is an uncommon condition with risks to sight and life. As a complication of maxillofacial injuries, the literature suggests this is only possible with fractures or direct inoculation, and there are no reports to the contrary. Here, we make the first report of a possible etiology by which orbital cellulitis developed in a 14-year-old boy even without skin breach or bony fractures; as well as a rare causative pathogen. He presented with facial abscess and progressive orbital cellulitis after blunt facial trauma, requiring functional endoscopic sinus surgery with needle aspiration of facial abscess externally. Cultures showed growth of Streptococcus constellatus/Parvimonas micra, and he received further antibiotics with full recovery.The pathophysiology of orbital cellulitis in this patient is attributed to vascular congestion and local pressure from maxillofacial contusion and maxillary hemoantrum, with impaired paranasal sinus ventilation encouraging anaerobic bacterial growth. Further progression led to facial abscess formation and intraorbital spread with orbital cellulitis. The pediatric demographic is injury-prone, and self-reporting of symptoms can be delayed. Hence, increased suspicion of complicated injuries and orbital cellulitis may be required when managing maxillofacial contusions so that prompt treatment can be given.

A phase II, multicenter, open-label, randomized trial of pegfilgrastim for patients with alcohol-associated hepatitis.

Background: In trials conducted in India, recombinant granulocyte colony stimulating factor (GCSF) improved survival in alcohol-associated hepatitis (AH). The aim of this trial was to determine the safety and efficacy of pegfilgrastim, a long-acting recombinant GCSF, in patients with AH in the United States. Methods: This prospective, randomized, open label trial conducted between March 2017 and March 2020 randomized patients with a clinical diagnosis of AH and a Maddrey discriminant function score ≥32 to standard of care (SOC) or SOC+pegfilgrastim (0.6 mg subcutaneously) on Day 1 and Day 8 (clinicaltrials.gov NCT02776059). SOC was 28 days of either pentoxifylline or prednisolone, as determined by the patient's primary physician. The second injection of pegfilgrastim was not administered if the white blood cell count exceeded 30,000/mm3 on Day 8. Primary outcome was survival at Day 90. Secondary outcomes included the incidence of acute kidney injury (AKI), hepatorenal syndrome (HRS), hepatic encephalopathy, or infections. Findings: The study was terminated early due to COVID19 pandemic. Eighteen patients were randomized to SOC and 16 to SOC+pegfilgrastim. All patients received prednisolone as SOC. Nine patients failed to receive a second dose of pegfilgrastin due to WBC > 30,000/mm3 on Day 8. Survival at 90 days was similar in both groups (SOC: 0.83 [95% confidence interval [CI]: 0.57-0.94] vs. pegfilgrastim: 0.73 [95% CI: 0.44-0.89]; p > 0.05; CI for difference: -0.18-0.38). The incidences of AKI, HRS, hepatic encephalopathy, and infections were similar in both treatment arms and there were no serious adverse events attributed to pegfilgrastim. Interpretation: This phase II trial found no survival benefit at 90 days among subjects with AH who received pegfilgrastim+prednisolone compared with subjects receiving prednisolone alone. Funding: was provided by the United States National Institutes of Health and National Institute on Alcohol Abuse and Alcoholism U01-AA021886 and U01-AA021884.

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.