Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial results.

Compromised vascular endothelial barrier function is a salient feature of diabetic complications such as sight-threatening diabetic macular edema (DME). Current standards of care for DME manage aspects of the disease, but require frequent intravitreal administration and are poorly effective in large subsets of patients. Here we provide evidence that an elevated burden of senescent cells in the retina triggers cardinal features of DME pathology and conduct an initial test of senolytic therapy in patients with DME. In cell culture models, sustained hyperglycemia provoked cellular senescence in subsets of vascular endothelial cells displaying perturbed transendothelial junctions associated with poor barrier function and leading to micro-inflammation. Pharmacological elimination of senescent cells in a mouse model of DME reduces diabetes-induced retinal vascular leakage and preserves retinal function. We then conducted a phase 1 single ascending dose safety study of UBX1325 (foselutoclax), a senolytic small-molecule inhibitor of BCL-xL, in patients with advanced DME for whom anti-vascular endothelial growth factor therapy was no longer considered beneficial. The primary objective of assessment of safety and tolerability of UBX1325 was achieved. Collectively, our data suggest that therapeutic targeting of senescent cells in the diabetic retina with a BCL-xL inhibitor may provide a long-lasting, disease-modifying intervention for DME. This hypothesis will need to be verified in larger clinical trials. ClinicalTrials.gov identifier: NCT04537884 .

Classification and Growth Rate of Chorioretinal Atrophy after Voretigene Neparvovec-Rzyl for RPE65-Mediated Retinal Degeneration.

PURPOSE: Classify the appearance and quantify the growth rate of chorioretinal atrophy in patients who received voretigene neparvovec-rzyl (VN) for RPE65-mediated retinal degeneration. DESIGN: Multicenter retrospective analysis. SUBJECTS: Patients who underwent subretinal VN injection at 5 institutions and demonstrated posterior-pole chorioretinal atrophy. METHODS: Ultrawidefield scanning laser ophthalmoscopy or color fundus photos were assessed before and after subretinal VN. Atrophy was defined as regions with ≥ 2 of the following: (1) partial or complete retinal pigment epithelial depigmentation; (2) round shape; (3) sharp margins; and (4) increased visibility of choroidal vessels. Atrophy was qualitatively classified into different subtypes. All atrophy was manually segmented. Linear mixed-effects models with random slopes and intercepts were fit using atrophy area and square root of atrophy area. MAIN OUTCOME MEASURES: Number of eyes with each atrophy pattern, and slopes of linear mixed-effects models. RESULTS: Twenty-seven eyes from 14 patients across 5 centers developed chorioretinal atrophy after subretinal VN. A mean of 5.8 ± 2.7 images per eye obtained over 2.2 ± 0.8 years were reviewed, and atrophy was categorized into touchdown (14 eyes), nummular (15 eyes), and perifoveal (12 eyes) subtypes. Fifteen eyes demonstrated > 1 type of atrophy. Thirteen of 14 patients demonstrated bilateral atrophy. The slopes of the mixed-effects models of atrophy area and square root of atrophy area (estimate ± standard error) were 1.7 ± 1.3 mm2/year and 0.6 ± 0.2 mm/year for touchdown atrophy, 5.5 ± 1.3 mm2/year and 1.2 ± 0.2 mm/year for nummular atrophy, and 16.7 ± 1.8 mm2/year and 2.3 ± 0.2 mm/year for perifoveal atrophy. The slopes for each type of atrophy were significantly different in the square root of atrophy model, which best fit the data (P < 0.05). CONCLUSIONS: Chorioretinal atrophy after subretinal VN for RPE65-mediated retinal degeneration developed according to a touchdown, nummular, and/or perifoveal pattern. Perifoveal atrophy grew the most rapidly, while touchdown atrophy grew the least rapidly. Understanding the causes of these findings, which are present in a minority of patients, merits further investigation. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Clinical and functional heterogeneity associated with the disruption of retinoic acid receptor beta.

PURPOSE: Dominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12. METHODS: We used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids. RESULTS: We found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators' recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment. CONCLUSION: Our study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity.

Disparities in Inherited Retinal Degenerations.

To review disparities in the field of inherited retinal degenerations to establish foundations for future discussions oriented toward finding possible solutions. A narrative overview of the literature. Despite collective efforts towards democratization of genetic testing and investigation, genetic databases containing primarily European populations are heavily relied upon. Access to specialized care and other resources is also still not available to all. Recognizing and addressing disparities and inequities within the field of inherited retinal degenerations will improve our care of these patients and our knowledge of their conditions.

Long-term outcomes of type 1 retinopathy of prematurity following monotherapy with bevacizumab: a Canadian experience.

OBJECTIVE: To report long-term structural, visual, and refractive outcomes after monotherapy with intravitreal bevacizumab injection. DESIGN: Cohort retrospective chart review. PARTICIPANTS: A total of 56 premature infants with type 1 retinopathy of prematurity. METHODS: This is a chart review at 2 Canadian institutions. Inclusion criteria were single injection of 0.625 mg  intravitreal bevacizumab and minimum age at last follow-up of 3 years. Primary outcome was retinal structure. Secondary outcomes were refractive error in spherical equivalent, monocular visual acuity, strabismus, and amblyopia. RESULTS: Fifty-six infants (101 eyes) met inclusion criteria. Mean birth weight was 707 ± 178 g (range, 420-1520 g). Mean gestational age was 25.0 ± 1.3 weeks (range, 22.9-29.7 weeks). Twenty-four eyes were in zone I (24%) and 77 in zone II (76%). Mean postmenstrual age at treatment was 36.9 ± 2.1 weeks (range, 32.8-42.0 weeks). At a mean age of 5.4 ± 1.6 years (range, 3.0-8.0 years), all eyes had a favourable structural outcome with no reactivation requiring treatment. Mean monocular visual acuity was 0.29 ± 0.27 logMAR (range, 0.0-1.3 logMAR; 89 of 101 eyes). Mean spherical equivalent was -1.98 ± 4.91 D (range, -16.63 to +5.38 D; 101 of 101 eyes). Prevalence of emmetropia (>-1.0 to ≤1 D) was 43.6%; low myopia (≥1.0 to <5 D) was 17.8%; high myopia (≥5 to <8 D) was 8.9 %; very high myopia (≥8.0 D) was 12.9%; and hyperopia (>1 D) was 16.8%. Twelve children (23%) had amblyopia, and 17 (32%) developed strabismus. CONCLUSIONS: All patients demonstrated a favourable structural outcome with a single bevacizumab injection without the need for additional laser. We suggest regular monitoring following regression of acute retinopathy of prematurity as an alternative to universal, preplanned delayed prophylactic laser treatment. Future studies to evaluate other aspects of visual function are needed.

Evolution of gender representation among Canadian OTL-HNS residents: a 27-year analysis.

BACKGROUND: The proportion of females enrolling into medical schools has been growing steadily. However, the representation of female residents among individual specialties has shown considerable variation. The purpose of this study was to compare the trends of gender representation in Otolaryngology - Head and Neck Surgery (OTL-HNS) residency programs with other specialty training programs in Canada. In order to contextualize these findings, a second phase of analysis examined the success rate of applicants of different genders to OTL-HNS residency programs. METHOD: Anonymized data were obtained from the Canadian Residency Matching Service (CaRMS) and from the Canadian Post-M.D. Education Registry (CAPER) from 1988 to 2014. The differences in gender growth rates were compared to other subspecialty programs of varying size. Descriptive analysis was used to examine gender representation among OTL-HNS residents across years, and to compare these trends with other specialties. Bayesian hierarchical models were fit to analyze the growth in program rates in OTL-HNS based on gender. RESULTS: CaRMS and CAPER data over a 27 year period demonstrated that OTL-HNS has doubled its female representation from 20% to 40% between 1990 and 1994 and 2010-2014. The difference in annual growth rate of female representation versus male representation in OTL-HNS over this time period was 2.7%, which was similar to other large specialty programs and surgical subspecialties. There was parity in success rates of female and male candidates ranking OTL-HNS as their first choice specialty for most years. CONCLUSIONS: Female representation in Canadian OTL-HNS residency programs is steadily increasing over the last 27 years. Large variation in female applicant acceptance rates was observed across Canadian universities, possibly attributable to differences in student body or applicant demographics. Factors influencing female medical student career selection to OTL-HNS require further study to mitigate disparities in gender representation and identify barriers to prospective female OTL-HNS applicants.

Long-term outcomes of sutureless 25-G+ pars-plana vitrectomy for the management of diabetic tractional retinal detachment.

PURPOSE: To evaluate the short- and long-term surgical and clinical outcomes in eyes with diabetic tractional retinal detachment (TRD) undergoing 25-G+ pars-plana vitrectomy (PPV). METHODS: A total of 238 patients were reviewed for inclusion in this study. A retrospective cohort study of 109 eyes of 73 patients operated on for diabetic TRD were included. All eyes received intraocular tamponade of air, sulfur hexafluoride, octofluropropane or silicone oil. All patients were followed up for a minimum period of one year. RESULTS: The mean age of all patients at surgery was 53.9 years ± 9.2, while the mean duration of diabetes was 18.7 ± 10.4 years. The mean length of follow-up was 923 ± 87 days after surgery (range, 432-1792 days). Thirty-two cases (29.3 %) had an associated rhegmatogenous component. Mean BCVA improved from logarithm minimum angle of resolution (logMAR) 1.17 (20/300) to 0.812 (20/130) (p < 0.05). All eyes underwent intraoperative laser photocoagulation. Primary, single-surgery anatomic reattachment was achieved in 99 eyes (91 %). Final anatomic attachment was achieved in 107 eyes (98 %). There was no statistically significant difference in primary or secondary re-attachment rate in terms of type of tamponade agent used. There were five cases of post-operative hypotony (≤5 mmHg) on postoperative day 1, while 11 eyes had IOP ≥ 30 mmHg. There were no cases of endophthalmitis in our cohort. CONCLUSIONS: 25G+ PPV provides for safe and effective repair of diabetic TRDs. Patients experienced positive functional and anatomic outcomes, with no significant intraoperative complications and minimal postoperative sequelae.