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Cilia are evolutionarily conserved hair-like structures with a wide spectrum of key biological roles, and their dysfunction has been linked to a growing class of genetic disorders, known collectively as ciliopathies. Many strides have been made towards deciphering the molecular causes for these diseases, which have in turn expanded the understanding of cilia and their functional roles. One recently-identified ciliary gene is ARL2BP, encoding the ADP-Ribosylation Factor Like 2 Binding Protein. In this study, we have identified multiple ciliopathy phenotypes associated with mutations in ARL2BP in human patients and in a mouse knockout model. Our research demonstrates that spermiogenesis is impaired, resulting in abnormally shaped heads, shortened and mis-assembled sperm tails, as well as in loss of axonemal doublets. Additional phenotypes in the mouse included enlarged ventricles of the brain and situs inversus. Mouse embryonic fibroblasts derived from knockout animals revealed delayed depolymerization of primary cilia. Our results suggest that ARL2BP is required for the structural maintenance of cilia as well as of the sperm flagellum, and that its deficiency leads to syndromic ciliopathy.

Photoreceptors are the most numerous and metabolically demanding cells in the retina. Their primary nutrient source is the choriocapillaris, and both the choriocapillaris and photoreceptors require trophic and functional support from retinal pigment epithelium (RPE) cells. Defects in RPE, photoreceptors, and the choriocapillaris are characteristic of age-related macular degeneration (AMD), a common vision-threatening disease. RPE dysfunction or death is a primary event in AMD, but the combination(s) of cellular stresses that affect the function and survival of RPE are incompletely understood. Here, using mouse models in which hypoxia can be genetically triggered in RPE, we show that hypoxia-induced metabolic stress alone leads to photoreceptor atrophy. Glucose and lipid metabolism are radically altered in hypoxic RPE cells; these changes impact nutrient availability for the sensory retina and promote progressive photoreceptor degeneration. Understanding the molecular pathways that control these responses may provide important clues about AMD pathogenesis and inform future therapies.

Phototransduction is accomplished in the retina by photoreceptor neurons and retinal pigment epithelium (RPE) cells. Photoreceptors rely heavily on the RPE, and death or dysfunction of RPE is characteristic of age-related macular degeneration (AMD), a very common neurodegenerative disease for which no cure exists. RPE replacement is a promising therapeutic intervention for AMD, and large numbers of RPE cells can be generated from pluripotent stem cells. However, questions persist regarding iPSC-derived RPE (iPS-RPE) viability, immunogenicity, and tumorigenesis potential. We showed previously that iPS-RPE prevent photoreceptor atrophy in dystrophic rats up until 24 weeks after implantation. In this follow-up study, we longitudinally monitored the same implanted iPS-RPE, in the same animals. We observed no gross abnormalities in the eyes, livers, spleens, brains, and blood in aging rats with iPSC-RPE grafts. iPS-RPE cells that integrated into the subretinal space outlived the photoreceptors and survived for as long as 2 1/2 years while nonintegrating RPE cells were ingested by host macrophages. Both populations could be distinguished using immunohistochemistry and electron microscopy. iPSC-RPE could be isolated from the grafts and maintained in culture; these cells also phagocytosed isolated photoreceptor outer segments. We conclude that iPS-RPE grafts remain viable and do not induce any obvious associated pathological changes.

Purpose: Dual inhibition of angiopoietin-2 and VEGF-A with faricimab (Vabysmo) offers excellent visual acuity gains with strong durability in patients with diabetic macular edema (ME) and neovascular age-related macular degeneration. The phase III BALATON/COMINO (NCT04740905/NCT04740931) trials will investigate the efficacy, safety, and durability of faricimab in patients with ME due to retinal vein occlusion (RVO). Design: Two identically designed global, randomized, double-masked, active comparator–controlled studies. Participants: Anti-VEGF treatment-naive patients with branch, central, or hemiretinal RVO. Methods: Patients were randomized to 6 monthly injections of faricimab 6.0 mg or aflibercept 2.0 mg. From weeks 24 to 72, all patients received faricimab 6.0 mg administered in up to 16-week intervals using an automated treatment algorithm to generate a treat-and-extend–based personalized treatment interval dosing regimen. Personalized treatment interval adjustments were based on changes in central subfield thickness (CST) and best-corrected visual acuity (BCVA). Main Outcome Measures: Primary end point was noninferiority of faricimab versus aflibercept in mean change from baseline in BCVA (week 24; noninferiority margin: 4 letters). Secondary end points (weeks 0–24) were mean change from baseline in BCVA, CST, and National Eye Institute Visual Function Questionnaire 25 composite score; proportion of patients gaining or avoiding loss of ≥ 15/≥ 10/≥ 5/> 0 letters. Secondary end points (weeks 24–72) were treatment durability (week 68); continuation of weeks 0 to 24 end points. Ocular/nonocular adverse events will be assessed. Results: In total, 1282 patients across 22 countries were enrolled (BALATON, 553 patients, 149 centers; COMINO, 729 patients, 193 centers). Conclusions: Using a novel automated interval algorithm, BALATON/COMINO will evaluate the efficacy and safety of faricimab for ME secondary to RVO and provide key insights into how to personalize treatment. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.