Development of self-healing hydrogels to support choroidal endothelial cell transplantation for the treatment of early age related macular degeneration.

In retinal diseases such as age-related macular degeneration (AMD) and choroideremia, a key pathophysiologic step is loss of endothelial cells of the choriocapillaris. Repopulation of choroidal vasculature early in the disease process may halt disease progression. Prior studies have shown that injection of donor cells in suspension results in significant cellular efflux and poor cell survival.

Elevation of Granulocyte Colony Stimulating Factor in Human AMD Donor RPE-Choroid.

Purpose: Choroidal inflammation, complement deposition, and accumulation of C-reactive protein (CRP) are involved in age-related macular degeneration (AMD) pathology. The pro-inflammatory signals that regulate immune cell recruitment in the choroid of patients with AMD remain to be determined. We performed cytokine profiling of human AMD and age-matched control donor tissue to identify inflammatory molecules upregulated in AMD tissue.

Ghost vessels in the eye: Cell free choriocapillaris domains in atrophic age-related macular degeneration.

The choriocapillaris is a dense vascular bed in the inner choroid that supplies the photoreceptor cells and retinal pigment epithelium (RPE). While loss of choriocapillaris density has been described in association with age-related macular degeneration (AMD), whether these changes are primary or secondary to RPE degenerative changes in AMD has been debated. In this study we characterized choriocapillaris loss by quantifying "ghost" vessels in a series of 99 human donor maculae labeled with the UEA-I lectin, and found significant increases in early-intermediate AMD and a greater difference in geographic atrophy in areas with intact RPE.

METTL23 Variants and Patients With Normal-Tension Glaucoma.

Importance: This research confirms and further establishes that pathogenic variants in a fourth gene, METTL23, are associated with autosomal dominant normal-tension glaucoma (NTG).

Objective: To determine the frequency of glaucoma-causing pathogenic variants in the METTL23 gene in a cohort of patients with NTG from Iowa.

Design, Setting, And Participants: This case-control study took place at a single tertiary care center in Iowa from January 1997 to January 2024, with analysis occurring between January 2023 and January 2024.

Progressive inner retinal neurodegeneration in non-proliferative macular telangiectasia type 2.

Purpose: Patients with non-proliferative macular telangiectasia type 2 (MacTel) have ganglion cell layer (GCL) and nerve fibre layer (NFL) loss, but it is unclear whether the thinning is progressive. We quantified the change in retinal layer thickness over time in MacTel with and without diabetes.

Methods: In this retrospective, multicentre, comparative case series, subjects with MacTel with at least two optical coherence tomographic (OCT) scans separated by >9 months OCTs were segmented using the Iowa Reference Algorithms.

Belzutifan in Individuals with von Hippel-Lindau Retinal Hemangioblastomas: Institutional Experience and Review of the Literature.

Introduction: The systemic HIF-2 alpha inhibitor, belzutifan, has been approved for use in patients with von Hippel-Lindau disease (VHL)-associated renal cell carcinoma, central nervous system (CNS) hemangioblastomas, and pancreatic neuroendocrine tumors. This drug has also shown promise in controlling VHL retinal hemangioblastomas (RHs), but little work has been published on the use of the drug in this setting.

Methods: We conducted a retrospective review of patients with VHL-associated RHs followed by the retina service at our institution who were treated with systemic belzutifan.

NR2E3 loss disrupts photoreceptor cell maturation and fate in human organoid models of retinal development.

While dysfunction and death of light-detecting photoreceptor cells underlie most inherited retinal dystrophies, knowledge of the species-specific details of human rod and cone photoreceptor cell development remains limited. Here, we generated retinal organoids carrying retinal disease-causing variants in NR2E3, as well as isogenic and unrelated controls. Organoids were sampled using single-cell RNA sequencing (scRNA-Seq) across the developmental window encompassing photoreceptor specification, emergence, and maturation.

High Dynamic Range Image Processing for Retinal Color Fundus Photography.

Background And Objective: Color fundus photography is an important imaging modality that is currently limited by a narrow dynamic range. We describe a post-image processing technique to generate high dynamic range (HDR) retinal images with enhanced detail.

Patients And Methods: This was a retrospective, observational case series evaluating fundus photographs of patients with macular pathology.

A Retrospective Longitudinal Study of 460 Patients with ABCA4-Associated Retinal Disease.

Purpose: To investigate the distribution of genotypes and natural history of ABCA4-associated retinal disease in a large cohort of patients seen at a single institution.

Design: Retrospective, single-institution cohort review.

Participants: Patients seen at the University of Iowa between November 1986 and August 2022 clinically suspected to have disease caused by sequence variations in ABCA4.

CRISPRi-Mediated Treatment of Dominant Rhodopsin-Associated Retinitis Pigmentosa.

Rhodopsin () mutations such as Pro23His are the leading cause of dominantly inherited retinitis pigmentosa in North America. As with other dominant retinal dystrophies, these mutations lead to production of a toxic protein product, and treatment will require knockdown of the mutant allele. The purpose of this study was to develop a CRISPR-Cas9-mediated transcriptional repression strategy using catalytically inactive Cas9 (dCas9) fused to the Krüppel-associated box (KRAB) transcriptional repressor domain.

Using Goldmann Visual Field Volume to Track Disease Progression in Choroideremia.

Purpose: Choroideremia is an X-linked choroidopathy caused by pathogenic variants in the gene. It is characterized by the early appearance of multiple scotomas in the peripheral visual field that spread and coalesce, usually sparing central vision until late in the disease. These features make quantitative monitoring of visual decline particularly challenging.

Demonstration of the pathogenicity of a common non-exomic mutation in ABCA4 using iPSC-derived retinal organoids and retrospective clinical data.

Mutations in ABCA4 are the most common cause of Mendelian retinal disease. Clinical evaluation of this gene is challenging because of its extreme allelic diversity, the large fraction of non-exomic mutations, and the wide range of associated disease. We used patient-derived retinal organoids as well as DNA samples and clinical data from a large cohort of patients with ABCA4-associated retinal disease to investigate the pathogenicity of a variant in ABCA4 (IVS30 + 1321 A>G) that occurs heterozygously in 2% of Europeans.

GJA3 Genetic Variation and Autosomal Dominant Congenital Cataracts and Glaucoma Following Cataract Surgery.

Importance: The p.Asp67Tyr genetic variant in the GJA3 gene is responsible for congenital cataracts in a family with a high incidence of glaucoma following cataract surgery.

Objective: To describe the clinical features of a family with a strong association between congenital cataracts and glaucoma following cataract surgery secondary to a genetic variant in the GJA3 gene (NM_021954.

Automated human induced pluripotent stem cell colony segmentation for use in cell culture automation applications.

Human induced pluripotent stem cells (hiPSCs) have demonstrated great promise for a variety of applications that include cell therapy and regenerative medicine. Production of clinical grade hiPSCs requires reproducible manufacturing methods with stringent quality-controls such as those provided by image-controlled robotic processing systems. In this paper we present an automated image analysis method for identifying and picking hiPSC colonies for clonal expansion using the CellX robotic cell processing system.

GENE EXPRESSION WITHIN A HUMAN CHOROIDAL NEOVASCULAR MEMBRANE USING SPATIAL TRANSCRIPTOMICS.

Macular neovascularization is a relatively common and potentially visually devastating complication of age-related macular degeneration. In macular neovascularization, pathologic angiogenesis can originate from either the choroid or the retina, but we have limited understanding of how different cell types become dysregulated in this dynamic process. In this study, we performed spatial RNA sequencing on a human donor eye with macular neovascularization as well as a healthy control donor.

Long-term functional and structural outcomes in X-linked retinoschisis: implications for clinical trials.

Introduction: X-linked retinoschisis (XLRS) is an inherited retinal disease (IRD) caused by pathogenic mutations in the retinoschisin gene, . Affected individuals develop retinal layer separation, leading to loss of visual acuity (VA). Several XLRS gene therapy trials have been attempted but none have met their primary endpoints.

Thrombospondin Mutations and Patients With Primary Congenital Glaucoma in a United States Population.

Mutations in the thrombospondin 1 ( THBS1 ) gene have been previously reported in primary congenital glaucoma (PCG) pedigrees that exhibit autosomal dominant inheritance with low penetrance. We sought to determine the role of THBS1 mutations in a cohort of 20 patients with PCG and 362 normal controls from Iowa using a combination of Sanger sequencing and whole exome sequencing. We detected 16 different THBS1 variants, including 4 rare, nonsynonymous variants (p.

Multimodal single-cell analysis of nonrandom heteroplasmy distribution in human retinal mitochondrial disease.

Variants within the high copy number mitochondrial genome (mtDNA) can disrupt organelle function and lead to severe multisystem disease. The wide range of manifestations observed in patients with mitochondrial disease results from varying fractions of abnormal mtDNA molecules in different cells and tissues, a phenomenon termed heteroplasmy. However, the landscape of heteroplasmy across cell types within tissues and its influence on phenotype expression in affected patients remains largely unexplored.

Propensity of Patient-Derived iPSCs for Retinal Differentiation: Implications for Autologous Cell Replacement.

Prior to use, newly generated induced pluripotent stem cells (iPSC) should be thoroughly validated. While excellent validation and release testing assays designed to evaluate potency, genetic integrity, and sterility exist, they do not have the ability to predict cell type-specific differentiation capacity. Selection of iPSC lines that have limited capacity to produce high-quality transplantable cells, places significant strain on valuable clinical manufacturing resources.

Left-sided valvular heart disease and retinopathy in a 38-year-old woman with attenuated mucopolysaccharidosis: a case report.

Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders caused by deficient levels and/or activity of glycosaminoglycan (GAG)-degradative enzymes. MPS are characterized by accumulation of the mucopolysaccharides heparan sulfate, dermatan sulfate, keratan sulfate, or chondroitin sulfate in tissues. We report the case of a 38-year-old woman with a history of joint restriction and retinitis pigmentosa who developed bivalvular heart failure requiring surgery.

Modeling rod and cone photoreceptor cell survival in vivo using optical coherence tomography.

Many retinal diseases involve the loss of light-sensing photoreceptor cells (rods and cones) over time. The severity and distribution of photoreceptor loss varies widely across diseases and affected individuals, so characterizing the degree and pattern of photoreceptor loss can clarify pathophysiology and prognosis. Currently, in vivo visualization of individual photoreceptors requires technology such as adaptive optics, which has numerous limitations and is not widely used.