Addressing Challenges in Developing Treatments for Inherited Retinal Diseases: Recommendations From the Third Monaciano Symposium.

Over the past decade, efforts focused on developing genetic therapies for inherited retinal diseases have advanced steadily to clinical trials and the development of a treatment, fueling optimism for the potential of precision medicines to provide safe and effective therapies for these rare conditions. Although several ongoing programs remain poised for success, numerous challenges have negatively impacted the ability to obtain regulatory approvals. The present position paper briefly summarizes recent advances and challenges in developing therapeutics for inherited retinal diseases, and presents a set of recommendations for moving the field forward.

Incidence and Impact of Outer Retinal Folds After Pars Plana Vitrectomy for Primary Rhegmatogenous Retinal Detachment Repair.

Purpose: To determine the incidence, risk factors, and visual impact of outer retinal fold formation after pars plana vitrectomy (PPV) for macula-involving rhegmatogenous retinal detachment (RRD).

Methods: A retrospective cohort study was performed of patients who had PPV with or without scleral buckling between 2011 and 2021 at a single tertiary referral center. Inclusion criteria were macular optical coherence tomography (OCT) performed within 6 weeks of PPV.

Neuroprotection of photoreceptors by combined inhibition of both Fas and autophagy pathways in P23H mice.

The P23H variant of rhodopsin (RHO) is a common cause of autosomal dominant retinitis pigmentosa (adRP). Our previous data have shown that both the Fas (CD95) death receptor and hyperactivation of autophagy contribute to photoreceptor (PR) death in a mouse model of P23H-RHO adRP. Individually, inhibition of Fas or suppression of autophagy flux improves PR survival and function.

Designing the next generation of clinical trials in intermediate AMD-a consensus driven, pragmatic, proof of concept early intervention study.

A greater understanding of the pathophysiology of AMD has yielded potential therapeutic strategies for slowing vision loss. Structural imaging biomarkers and novel functional outcomes, both under intensive study as surrogate endpoints in AMD clinical trials, are new granular tools needed to assess disease progression and follow response to therapy. These advances have created, for the first time, the possibility to intervene early in AMD, and to measure success in a time frame feasible for clinical trials.

Remote Preconditioning Provides Protection Against Retinal Cell Death From Retinal Detachment.

Purpose: Remote preconditioning involves injury to a tissue that results in protection to a subsequent injury in a distal tissue. Here, we investigated the impact of remote preconditioning on retinal detachment (RD) injury, hypothesizing that a previous contralateral RD would protect the fellow retina against inflammation and cell death following its detachment.

Methods: RD was created in adult C57BL/6J mice with subretinal sodium hyaluronate injection.

Promising therapeutic targets for neuroprotection in retinal disease.

Purpose Of Review: Neurodegeneration is a common endpoint of various blinding retinal diseases. Yet, despite exciting advances in disease treatment, there continues to exist a critical need for the development of neuroprotective strategies to prevent retinal cell death. Here, we summarize the recent advances in neuroprotective strategies.

Multimodal Imaging Characteristics and Correlation to Outcomes in Patients With Central Retinal Artery Occlusion Presenting to a Large Academic Center.

Purpose: To characterize a large modern cohort of patients with central retinal artery occlusion (CRAO) by describing presenting features and outcomes relating to manually segmented optical coherence tomography (OCT) features, angiographic reperfusion, and visual recovery.

Design: Retrospective clinical cohort study.

Methods: Patients with CRAO (ICD-10: H34.

ER Stress and Mitochondrial Perturbations Regulate Cell Death in Retinal Detachment: Exploring the Role of HIF1α.

Purpose: Retinal detachment (RD) leads to photoreceptor (PR) hypoxia due to separation from the retinal pigment epithelium (RPE). Hypoxia stabilizes retinal hypoxia-inducible factor 1-alpha (HIF1α), crucial for PR survival during RD. This study explores the regulatory role of HIF1α in PR cell survival pathways during RD.

Preservation of retinal structure and function in two mouse models of inherited retinal degeneration by ONL1204, an inhibitor of the Fas receptor.

Due to the large number of genes and mutations that result in inherited retinal degenerations (IRD), there has been a paucity of therapeutic options for these patients. There is a large unmet need for therapeutic approaches targeting shared pathophysiologic pathways in a mutation-independent manner. The Fas receptor is a major activator and regulator of retinal cell death and inflammation in a variety of ocular diseases.

The mouse retinal pigment epithelium mounts an innate immune defense response following retinal detachment.

The retinal pigment epithelium (RPE) maintains photoreceptor viability and function, completes the visual cycle, and forms the outer blood-retinal barrier (oBRB). Loss of RPE function gives rise to several monogenic retinal dystrophies and contributes to age-related macular degeneration. Retinal detachment (RD) causes separation of the neurosensory retina from the underlying RPE, disrupting the functional and metabolic relationships between these layers.

NO EFFECT OF REAL-WORLD UNIVERSAL FACE MASKING ON POST-INTRAVITREAL INJECTION ENDOPHTHALMITIS RATE AT A SINGLE TERTIARY ACADEMIC CENTER.

Purpose: To determine whether universal masking during COVID-19 altered rate and outcomes of postinjection endophthalmitis.

Methods: Retrospective, single-site, comparative, cohort study. Eyes diagnosed with endophthalmitis within 4 weeks of intravitreal injection at the University of Michigan from August 1, 2012, to November 15, 2022, were identified.

An Evaluation of the Repeatability of Visual Function Following Surgical Repair of Macula-Off Rhegmatogenous Retinal Detachment.

Purpose: To evaluate the reliability and reproducibility of visual function assessments for patients with macula-off rhegmatogenous retinal detachment (RRD).

Methods: This prospective study included patients with unilateral macula-off RRD of <10-day duration successfully treated with a single, uncomplicated surgery at least 1 year following repair. Visual function assessments were performed at time of enrollment and 1 month later.

Retinal Detachments after Open-Globe Injury: Risk Factors and Outcomes.

Purpose: To identify risk factors for retinal detachment (RD) after open-globe injury (OGI) and evaluate outcomes of RD repair after OGI.

Design: Case-control study.

Participants: Overall, 769 patients presented with 786 OGIs, which were surgically managed with ≥ 30 days of follow-up.

Increase in Retinal Detachment Repair Over a Ten-Year Period at an Academic Center Compared to National Trends.

Background And Objective: This study aimed to determine whether cases of surgical retinal detachment (RD) repair at a tertiary care center from January 1, 2011 to December 31, 2020 increased proportionately to macular surgery cases as a control and to national trends.

Patients And Methods: Current Procedural Terminology codes were used to identify cases of primary RD repair (67107, 67108), complex RD repair (67113), pneumatic retinopexy (67110), and vitrectomy with membrane peeling (67041, 67042) at an academic center and in the Part B National Summary Data Files. Numbers of cases and mean case times at the academic center were determined.

Clinical Characteristics and Visual Outcomes of Acute Syphilitic Posterior Placoid Chorioretinopathy.

Purpose: To evaluate presenting features and visual outcomes in eyes with acute syphilitic posterior placoid chorioretinopathy (ASPPC).

Design: Retrospective cohort study.

Subjects: A total of 24 eyes of 17 adult patients with ASPPC.

Risk Factors for Enucleation Following Open Globe Injury: A 17-Year Experience.

Purpose: At the time of open globe injury (OGI), it may be difficult for clinicians to predict which eyes are at highest risk for requiring enucleation. We performed a 17-year retrospective cohort study to report outcomes and risk factors for enucleation following open globe injuryto better aid clinicians counseling patients at OGI diagnosis.

Methods: A retrospective cohort study of all patients who presented to the University of Michigan with open globe injury (OGI) and were surgically managed between January 2000 and July 2017 was conducted.

Hypoxia-Inducible Factor-1α in Rods Is Neuroprotective Following Retinal Detachment.

Purpose: Following retinal detachment (RD) photoreceptors (PRs) sustain hypoxic stress and eventually die. Hypoxia-inducible factor-1α (HIF-1α) plays a central role in cellular adaptation to hypoxia. The purpose of this study is to determine the necessity of HIF-1α on PR cell survival after RD.

Loss of Fas Receptor Function Preserves Photoreceptor Structure and Function in Two Mouse Models of Inherited Retinal Degeneration.

Purpose: The genetic heterogeneity of inherited retinal degeneration (IRD) has limited the development of mutation-specific therapies, necessitating the development of therapeutic approaches targeting broadly shared pathophysiologic pathways. The Fas receptor has been reported as a contributor to retinal cell death and inflammation in a wide variety of ocular diseases. The purpose of this study was to assess targeting the Fas pathway as a novel mutation-independent approach to improve photoreceptor survival in IRD.

Endophthalmitis, Visual Outcomes, and Management Strategies in Eyes with Intraocular Foreign Bodies.

Purpose: Ocular trauma with intraocular foreign body (IOFB) can have devastating visual consequences. Management and antimicrobial strategies remain variable due to the infrequency and heterogeneity of presentation. Our goal was to identify risk factors for endophthalmitis and poor visual outcomes in cases of IOFB and investigate management strategies.

Quantitative contrast sensitivity test to assess visual function in central serous chorioretinopathy.

Background: To characterise the contrast sensitivity function (CSF) in central serous chorioretinopathy (CSCR) compared with healthy controls using novel computerised contrast sensitivity (CS) testing with active learning algorithms.

Methods: Prospective observational study measuring CSF in CSCR eyes and controls using the Manifold Platform (Adaptive Sensory Technology, San Diego, California). Mixed effects multivariate regression models were used.

Cell Death in AMD: The Rationale for Targeting Fas.

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the developed world. While great advances have been made in the treatment of the neovascular ("wet") form of the disease, there is still a significant need for therapies that prevent the vision loss associated with the advanced forms of dry, atrophic AMD. In this atrophic form, retinal pigment epithelial (RPE) and photoreceptor cell death is the ultimate cause of vision loss.

Loss of αA or αB-Crystallin Accelerates Photoreceptor Cell Death in a Mouse Model of P23H Autosomal Dominant Retinitis Pigmentosa.

Inherited retinal degenerations (IRD) are a leading cause of visual impairment and can result from mutations in any one of a multitude of genes. Mutations in the light-sensing protein rhodopsin (RHO) is a leading cause of IRD with the most common of those being a missense mutation that results in substitution of proline-23 with histidine. This variant, also known as P23H-RHO, results in rhodopsin misfolding, initiation of endoplasmic reticulum stress, the unfolded protein response, and activation of cell death pathways.