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The 2023 Lasker-DeBakey Clinical Medical Research Award has been awarded to James G. Fujimoto (Massachusetts Institute of Technology [MIT]), David Huang (Oregon Health and Science University-Casey Eye Institute), and Eric [...]

Patient-derived induced pluripotent stem cells (iPSCs) provide a powerful tool for identifying cellular and molecular mechanisms of disease. Macular telangiectasia type 2 (MacTel) is a rare, late-onset degenerative retinal disease with an extremely heterogeneous genetic architecture, lending itself to the use of iPSCs. Whole-exome sequencing screens and pedigree analyses have identified rare causative mutations that account for less than 5% of cases. Metabolomic surveys of patient populations and GWAS have linked MacTel to decreased circulating levels of serine and elevated levels of neurotoxic 1-deoxysphingolipids (1-dSLs). However, retina-specific, disease- contributing factors have yet to be identified. Here, we used iPSC-differentiated retinal pigmented epithelial (iRPE) cells derived from donors with or without MacTel to screen for novel cell-intrinsic pathological mechanisms. We show that MacTel iRPE cells mimicked the low serine levels observed in serum from patients with MacTel. Through RNA-Seq and gene set enrichment pathway analysis, we determined that MacTel iRPE cells are enriched in cellular stress pathways and dysregulation of central carbon metabolism. Using respirometry and mitochondrial stress testing, we functionally validated that MacTel iRPE cells had a reduction in mitochondrial function that was independent of defects in serine biosynthesis and 1-dSL accumulation. Thus, we identified phenotypes that may constitute alternative disease mechanisms beyond the known serine/sphingolipid pathway., Introduction Complex diseases of aging provide unique challenges for the identification of specific disease-causing genetic variants and associated cellular dysfunctions using traditional genetic approaches. Disease modeling using iPSCs is a [...]

In multiple neurodegenerative diseases, including age-related macular degeneration, retinitis pigmentosa, and macular telangiectasia type 2 (MacTel), retinal pigment epithelial (RPE)-cells proliferate and migrate into the neuroretina, forming intraretinal pigment plaques. Though these pigmentary changes are hallmarks of disease progression, it is unknown if their presence is protective or detrimental. Here, we first evaluated the impact of pigment plaques on vascular changes and disease progression in MacTel. In a retrospective, longitudinal study, we analyzed multimodal retinal images of patients with MacTel and showed that pigment plaques were associated with decreased vascular leakage and stabilized neovascular growth. We then modeled the underlying pathomechanisms of pigment plaque formation in aberrant neovascular growth using the very-low-density lipoprotein receptor mutant (Vldlr−/−) mouse. Our data indicated that during RPE-proliferation, migration and accumulation along neovessels RPE-cells underwent epithelial-mesenchymal transition (EMT). Pharmacologic inhibition of EMT in Vldlr−/− mice decreased pigment coverage, and exacerbated neovascular growth and vascular leakage. Our findings indicate that the proliferation, migration and perivascular accumulation of RPE-cells stabilize vascular proliferation and exudation, thereby exerting a protective effect on the diseased retina. We conclude that interfering with this "natural repair mechanism" may have detrimental effects on the course of the disease and should thus be avoided. [ABSTRACT FROM AUTHOR]

Aims To identify morphological characteristics preceding the development of exudative neovascularisation secondary to Macular Telangiectasia type 2 (MacTel) using multimodal retinal imaging. Methods In this retrospective study, eyes with a minimum observation period of 6 months prior to the de novo diagnosis of an exudative neovascularisation secondary to MacTel were analysed. Morphological changes preceding the formation of neovascularisation were evaluated using colour fundus photography, infrared imaging, fluorescein angiography, macular pigment measurement and optical coherence tomography (OCT). OCT-angiography (OCT-A) images were additionally available in a subset of patients. Results Twenty eyes from 20 patients were examined over a median period of 17 months (range: 6-100 months). Eyes were characterised by an accelerated progression of ellipsoid zone loss (median of 0.013 mm2/month), increased thickness of the temporal parafovea and hyper-reflective lesions on OCT. The latter underwent morphological changes preceding the development of exudative neovascularisation, including an increase in size and density, and expansion to outer retinal layers and the retinal pigment epithelium. All eyes showed a foveal depletion of macular pigment. On OCT-A, a focal increase in blood flow was observed at the level of the outer retina/choriocapillaris, and retinal-retinal and retinal-choroidal anastomoses preceded the formation of exudative neovascularisation. Conclusions Multimodal imaging allows the identification of prognostic morphological features preceding the formation of exudative neovascularisation in MacTel. Eyes exhibiting these characteristics should be monitored closely and patients should be alert for emergent symptoms in order to detect and treat neovascularisation early and, thereby, prevent irreversible visual loss. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the role of right-angled vessels (RAVs) during disease progression in macular telangiectasia type 2 (MacTel). Methods In this study, 100 eyes of 52 patients and 52 eyes of 26 age-related controls were examined using fundus photography, spectral-domain optical coherence tomography (SD-OCT), OCT angiography (OCT-A) and fundus fluorescein angiography (FFA). Two masked readers graded fundus photographs of patients' eyes into five disease stages according to Gass and Blodi, and evaluated all eyes for the presence of RAVs. If RAVs were present, their course and origin (arterial vs venous) was evaluated with OCT-A and FFA, respectively. Additionally, we looked for morphological correlates of these vessels on SD-OCT scans. Neovascular eyes were analysed for the presence of RAVs and for morphological changes on formation of neovascularisations (NVs). Results In OCT-A, RAVs were already detectable in eyes with early stages (1 to 2), could be tracked from superficial to outer retinal layers and were shown to form anastomoses in the outer retina with disease progression. These vessels were of both arterial and venous origin as shown by early phase FFA. Dilated capillaries and RAVs in OCT-A corresponded to hyper-reflective alterations of the outer retina on SD-OCT scans. In 19/19 eyes, NVs were associated with the presence of RAVs, and RAVs were shown to directly connect to neovascular complexes and to undergo morphological changes upon NV formation. Conclusions The results emphasise the role of RAVs during disease progression from an early stage on and demonstrate their involvement in the development of secondary NVs in MacTel. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the utility of optical coherence tomography-angiography (OCT-A) for monitoring activity, progression and response to therapy of neovascularisations (NVs) secondary to macular telangiectasia type 2 (MacTel). Methods In a retrospective analysis, eyes with NVs secondary to MacTel were reviewed over a period of =8 months. Examinations at monthly intervals included visual acuity testing, dilated funduscopy, spectral domain-OCT and OCT-A. Eyes were treated with intravitreal VEGF (vascular endothelial growth factor)-inhibitors following a pro-re-nata (PRN) regime, and treatment decisions were based on morphological signs of activity as determined by B-scan OCT and funduscopy. Signs of neovascular activity were defined as an increase in retinal thickness, presence/increase of intraretinal/subretinal fluid and haemorrhages. Results A total of 19 eyes from 17 patients were analysed. Patients were evaluated over a mean period of 13.4 months (range: 8.9 to 24.2). OCT-A permitted the monitoring of both treatment effects (regression) and progression (growth) of NVs, but not neovascular activity. The growth of neovascular vessels was detectable in OCT-A before signs of activity occurred on OCT. NVs showed a progressive growth over time despite PRN-treatment and preferentially grew and extended within areas characterised by a focal reduction of choriocapillaris perfusion. Conclusions The results indicate that OCT-A represents a useful imaging modality for monitoring NV-progression and treatment effects in MacTel. We demonstrate its advantages over conventional B-scan OCT imaging, including an earlier detection of NV-progression, and propose an adjustment of the current OCT-controlled PRN treatment regime in order to prevent NV-progression and subsequent functional loss in neovascular MacTel. [ABSTRACT FROM AUTHOR]

In multiple neurodegenerative diseases, including age-related macular degeneration, retinitis pigmentosa, and macular telangiectasia type 2 (MacTel), retinal pigment epithelial (RPE)-cells proliferate and migrate into the neuroretina, forming intraretinal pigment plaques. Though these pigmentary changes are hallmarks of disease progression, it is unknown if their presence is protective or detrimental.Here, we first evaluated the impact of pigment plaques on vascular changes and disease progression in MacTel. In a retrospective, longitudinal study, we analyzed multimodal retinal images of patients with MacTel and showed that pigment plaques were associated with decreased vascular leakage and stabilized neovascular growth. We then modeled the underlying pathomechanisms of pigment plaque formation in aberrant neovascular growth using the very-low-density lipoprotein receptor mutant (Vldlr -/- ) mouse. Our data indicated that during RPE-proliferation, migration and accumulation along neovessels RPE-cells underwent epithelial-mesenchymal transition (EMT). Pharmacologic inhibition of EMT in Vldlr -/- mice decreased pigment coverage, and exacerbated neovascular growth and vascular leakage.Our findings indicate that the proliferation, migration and perivascular accumulation of RPE-cells stabilize vascular proliferation and exudation, thereby exerting a protective effect on the diseased retina. We conclude that interfering with this "natural repair mechanism" may have detrimental effects on the course of the disease and should thus be avoided., Competing Interests: Declarations. Ethical approval: The studies were approved by the local ethics committees at each participating study site (Comité consultatif de protection des personnes dans la recherche biomédicale (CCPPRB); Human Research Ethics Committee (HREC); London City Road & Hampstead Research Ethics Committee; Sterling Institutional Review Board; Ethik-Kommission der Ärztekammer Westfalen-Lippe und der Medizinischen Fakultät der WWU Münster; The State of Israel Ministry of Health; The Chaim Sheba Medical Center; Ethik-Kommission - Medizinische Fakultät Bonn; University of Pennsylvania Institutional Review Board; Kantonale Ethikkommission Bern (KEK); University of Miami Human Subject Research Office), and were in adherence with the Declaration of Helsinki. All participants provided informed consent prior to participation. All animal experimental procedures were approved by The Scripps Research Institute Animal Care and Use Committee. Experiments were performed in accordance with the NIH Guide for the Care and Use of Laboratory Animals (National Academies Press, 2011). Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: Automated segmentation software in optical coherence tomography (OCT) devices is usually developed for and primarily tested on common diseases. Therefore segmentation accuracy of automated software can be limited in eyes with rare pathologies., Methods: We sought to develop a semisupervised deep learning segmentation model that segments 10 retinal layers and four retinal features in eyes with Macular Telangiectasia Type II (MacTel) using a small labeled dataset by leveraging unlabeled images. We compared our model against popular supervised and semisupervised models, as well as conducted ablation studies on the model itself., Results: Our model significantly outperformed all other models in terms of intersection over union on the 10 retinal layers and two retinal features in the test dataset. For the remaining two features, the pre-retinal space above the internal limiting membrane and the background below the retinal pigment epithelium, all of the models performed similarly. Furthermore, we showed that using more unlabeled images improved the performance of our semisupervised model., Conclusions: Our model improves segmentation performance over supervised models by leveraging unlabeled data. This approach has the potential to improve segmentation performance for other diseases, where labeled data is limited but unlabeled data abundant., Translational Relevance: Improving automated segmentation of MacTel pathology on OCT imaging by leveraging unlabeled data may enable more accurate assessment of disease progression, and this approach may be useful for improving feature identification and location on OCT in other rare diseases as well.

Purpose: The purpose of this study was to quantify hyper-reflective lesions on en face optical coherence tomography (OCT) and study its functional relevance in macular telangiectasia type 2 (MacTel)., Design: This was a retrospective, cross-sectional cohort study., Methods: Baseline image and functional data from participants of a phase II clinical trial (NCT01949324) that studied the effect of Ciliary Neurotrophic Factor in patients with MacTel were analyzed. The projection of hyper-reflectivity within different layers on OCT was used to generate an en face view and measure the en face size of hyper-reflectivity. Ellipsoid zone (EZ)-loss was additionally evaluated, and en face images were superimposed onto microperimetry sensitivity maps, allowing to estimate mean retinal sensitivity within areas displaying hyper-reflectivity and EZ-loss, respectively. Best-corrected visual acuity (BCVA) and reading speed were also analyzed., Results: Fifty-two eyes from 52 patients were analyzed. Hyper-reflectivity was present in 32 eyes (62%), and EZ-loss in 50 (96%) eyes. Mean lesion size was 0.11 mm² (range = 0.01-0.26) for hyper-reflectivity and 0.51 mm² (range = 0.02-1.34) for EZ-loss, and lesion sizes correlated strongly (Spearman r = 0.79, P < 0.001). Although both hyper-reflectivity and EZ-loss were associated with a significant decrease in retinal sensitivity, mean sensitivity thresholds differed significantly between lesions (0.9 dB vs. 16.3 dB; P < 0.001), indicating an almost complete loss of sensitivity in hyper-reflective areas. No correlations were found between the size of hyper-reflectivity and BCVA (r = 0.09) or reading speed (r = -0.17)., Conclusions: En face OCT can be used to quantify the area of hyper-reflective lesions in MacTel. Hyper-reflectivity in MacTel is associated with severe functional impairment, leading to an almost complete loss of retinal sensitivity as observed on microperimetry.

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