Bestrophinopathies: perspectives on clinical disease, Bestrophin-1 function and developing therapies DOI Creative Commons
S. Grewal, Joseph J. Smith, Amanda‐Jayne F. Carr

et al.

Therapeutic Advances in Ophthalmology, Journal Year: 2021, Volume and Issue: 13

Published: Jan. 1, 2021

Bestrophinopathies are a group of clinically distinct inherited retinal dystrophies that typically affect the macular region, an area synonymous with central high acuity vision. This spectrum disorders is caused by mutations in bestrophin1 (BEST1), protein thought to act as Ca2+-activated Cl- channel pigment epithelium (RPE) eye. Although bestrophinopathies rare, over 250 individual pathological have been identified BEST1 gene, many reported various clinical expressivity and incomplete penetrance. With no current treatments available for patients bestrophinopathies, understanding role cells pathways underlying disease has become priority. Induced pluripotent stem cell (iPSC) technology helping uncover mechanisms develop RPE diseases, like bestrophinopathies. Here, we provide comprehensive review pathophysiology highlight how patient-derived iPSC-RPE being used test new genomic therapies vitro.

Language: Английский

Human retinal pigment epithelial cells prefer proline as a nutrient and transport metabolic intermediates to the retinal side DOI Creative Commons
Jennifer R. Chao,

Kaitlen Knight,

Abbi L. Engel

et al.

Journal of Biological Chemistry, Journal Year: 2017, Volume and Issue: 292(31), P. 12895 - 12905

Published: June 15, 2017

Language: Английский

Citations

91
Dynamic lipid turnover in photoreceptors and retinal pigment epithelium throughout life DOI Creative Commons
Dominik Lewandowski, Christopher L. Sander, Aleksander Tworak

et al.

Progress in Retinal and Eye Research, Journal Year: 2021, Volume and Issue: 89, P. 101037 - 101037

Published: Dec. 29, 2021

The retinal pigment epithelium-photoreceptor interphase is renewed each day in a stunning display of cellular interdependence. While photoreceptors use photosensitive pigments to convert light into electrical signals, the RPE supports their function by phagocytizing shed photoreceptor tips, regulating blood retina barrier, and modulating inflammatory responses, as well regenerating 11-cis-retinal chromophore via classical visual cycle. These processes involve multiple protein complexes, tightly regulated ligand-receptors interactions, plethora lipids protein-lipids interactions. role maintaining healthy interplay between has not been fully delineated. In recent years, novel technologies have resulted major advancements understanding several facets this interplay, including involvement phagocytosis phagolysosome function, nutrient recycling, metabolic dependence two cell types. review, we aim integrate complex emphasizing dynamic exchange cells discuss how these are affected aging diseases.

Language: Английский

Citations

63
Scarless Genome Editing of Human Pluripotent Stem Cells via Transient Puromycin Selection DOI Creative Commons
Benjamin Steyer, Qian Bu, Evan Cory

et al.

Stem Cell Reports, Journal Year: 2018, Volume and Issue: 10(2), P. 642 - 654

Published: Jan. 4, 2018

Genome-edited human pluripotent stem cells (hPSCs) have broad applications in disease modeling, drug discovery, and regenerative medicine. We present characterize a robust method for rapid, scarless introduction or correction of disease-associated variants hPSCs using CRISPR/Cas9. Utilizing non-integrated plasmid vectors that express puromycin N-acetyl-transferase (PAC) gene, whose expression translation is linked to Cas9, we transiently select based on their early levels Cas9 protein. Under optimized conditions, co-delivery with single-stranded donor DNA enabled isolation clonal cell populations containing both heterozygous homozygous precise genome edits as little 2 weeks without requiring sorting high-throughput sequencing. Edited isolated this did not contain any detectable off-target mutations displayed expected functional phenotypes after directed differentiation. apply the approach variety genomic loci five hPSC lines cultured feeder feeder-free conditions.

Language: Английский

Citations

69
BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure DOI Creative Commons
Karina E Guziewicz, Artur V. Cideciyan, William A. Beltran

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2018, Volume and Issue: 115(12)

Published: March 5, 2018

Significance One of the most common forms monogenic macular degeneration worldwide is caused by dominant or recessive bestrophinopathies associated with mutations in BEST1 gene. Disease expression known to start a retina-wide electrophysiological defect leading localized vitelliform and atrophic lesions vision loss. To develop lasting therapies for this incurable disease, there need greater understanding early pathophysiology before lesion formation. Here we find that loss retinal pigment epithelium apical microvilli resulting microdetachment retina represent earliest features canine bestrophinopathies. We show light exposure expands, dark adaptation contracts, microdetachments. Subretinal adeno-associated virus-based gene therapy corrects both light-modulated

Language: Английский

Citations

69
Aberrant early endosome biogenesis mediates complement activation in the retinal pigment epithelium in models of macular degeneration DOI Open Access
Gulpreet Kaur, Li Xuan Tan, Gurugirijha Rathnasamy

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2018, Volume and Issue: 115(36), P. 9014 - 9019

Published: Aug. 20, 2018

Significance The first lines of communication between cells and the environment are early endosomes, which sort incoming cargo to regulate cell health. Endosomal abnormalities seen in neurodegenerative diseases, yet molecular mechanisms remain obscure. Here, using human donor disease models, we demonstrate that excess ceramide promotes expansion endosomes retinal pigment epithelium (RPE), a primary site injury Stargardt age-related maculopathies. Complement C3 uptake into enlarged subsequent cleavage is associated with abnormal mechanistic target rapamycin activity. Decreasing Food Drug Administration-approved drugs corrects endosomal defects prevents activation. Our studies establish how organelles modulate RPE complement activity, identify as drug for macular degenerations.

Language: Английский

Citations

67
Complement activation, lipid metabolism, and mitochondrial injury: Converging pathways in age-related macular degeneration DOI Creative Commons
Li Xuan Tan, Colin J. Germer, Nilsa La Cunza

et al.

Redox Biology, Journal Year: 2020, Volume and Issue: 37, P. 101781 - 101781

Published: Oct. 1, 2020

The retinal pigment epithelium (RPE) is the primary site of injury in non-neovascular age-related macular degeneration or dry AMD. Polymorphisms genes that regulate complement activation and cholesterol metabolism are strongly associated with AMD, but biology underlying disease-associated variants not well understood. Here, we highlight recent studies have used molecular, biochemical, live-cell imaging methods to elucidate mechanisms by which aging-associated insults conspire AMD genetic risk tip balance towards disease. We discuss how critical functions including lipid metabolism, autophagy, regulation, mitochondrial dynamics compromised RPE, a deeper understanding these has helped identify promising therapeutic targets preserve RPE homeostasis

Language: Английский

Citations

50
Human iPSC Modeling Reveals Mutation-Specific Responses to Gene Therapy in a Genotypically Diverse Dominant Maculopathy DOI Creative Commons

Divya Sinha,

Benjamin Steyer,

Pawan K. Shahi

et al.

The American Journal of Human Genetics, Journal Year: 2020, Volume and Issue: 107(2), P. 278 - 292

Published: July 23, 2020

Language: Английский

Citations

43
Mitochondria-dependent phase separation of disease-relevant proteins drives pathological features of age-related macular degeneration DOI Creative Commons
Nilsa La Cunza, Li Xuan Tan,

Thushara Thamban

et al.

JCI Insight, Journal Year: 2021, Volume and Issue: 6(9)

Published: April 6, 2021

Age-related macular degeneration (AMD) damages the retinal pigment epithelium (RPE), tissue that safeguards photoreceptor health, leading to irreversible vision loss. Polymorphisms in cholesterol and complement genes are implicated AMD, yet mechanisms linking risk variants RPE injury remain unclear. We sought determine how allelic apolipoprotein E transporter modulate homeostasis function. Using live-cell imaging, we show inefficient transport by AMD risk-associated ApoE2 increases ceramide, autophagic defects complement-mediated mitochondrial damage. Mitochondrial drives redox state-sensitive cysteine-mediated phase separation of ApoE2, forming biomolecular condensates could nucleate drusen. The protective ApoE4 isoform lacks these cysteines is resistant condensate formation. In Abca-/- Stargardt mice, dysfunction induces liquid-liquid p62/SQSTM1, a multifunctional protein regulates autophagy. Drugs decrease or ceramide prevent vitro vivo. donor RPE, fragmentation correlates with ApoE p62 condensates. Our studies demonstrate major genetic biological pathways converge upon mitochondria, identify stress-mediated as an important pathogenic mechanism promising therapeutic target AMD.

Language: Английский

Citations

37
Non-vasogenic cystoid maculopathies DOI Creative Commons
Alain Gaudric, Isabelle Audo, Catherine Vignal

et al.

Progress in Retinal and Eye Research, Journal Year: 2022, Volume and Issue: 91, P. 101092 - 101092

Published: Aug. 1, 2022

Besides cystoid macular edema due to a blood-retinal barrier breakdown, another type of spaces referred as non-vasogenic maculopathies (NVCM) may be detected on optical coherence tomography but not fluorescein angiography. Various causes disrupt retinal cell cohesion or impair pigment epithelium (RPE) and Müller functions in the maintenance dehydration, resulting formation. Tractional include vitreomacular traction, epiretinal membranes myopic foveoschisis. Surgical treatment does always allow space resorption. In inherited dystrophies, part disease X-linked retinoschisis enhanced S-cone syndrome, occur occasionally bestrophinopathies, retinitis pigmentosa allied diseases, congenital microphthalmia, choroideremia, gyrate atrophy Bietti crystalline dystrophy. telangiectasia 2, cavitations do depend fluid leakage from telangiectasia. affecting RPE function result NVCM such chronic central serous chorioretinopathy paraneoplastic syndromes. Non-exudative age degeneration also complicated by intraretinal absence leakage. these context loss. optic atrophy, including open-angle glaucoma, microcystoid inner nuclear layer retrograde transsynaptic degeneration. Lastly, drug toxicity induce maculopathy. Identifying multimodal imaging, angiography if needed, allows guiding diagnosis causative choosing adequate when available.

Language: Английский

Citations

20
Cell-cell interaction in the pathogenesis of inherited retinal diseases DOI Creative Commons

Xue Du,

Anna G. Butler,

Holly Y. Chen

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: March 4, 2024

The retina is part of the central nervous system specialized for vision. Inherited retinal diseases (IRD) are a group clinically and genetically heterogenous disorders that lead to progressive vision impairment or blindness. Although each disorder rare, IRD accumulatively cause blindness in up 5.5 million individuals worldwide. Currently, pathophysiological mechanisms not fully understood there limited treatment options available. Most caused by degeneration light-sensitive photoreceptors. Genetic mutations abrogate structure and/or function photoreceptors visual followed loss In healthy retina, structurally functionally interact with pigment epithelium (RPE) Müller glia (MG) maintain homeostasis. Multiple photoreceptor as major phenotype RPE- MG-associated genes. Recent studies also reveal compromised MG RPE ubiquitously expressed ciliary Therefore, could be direct consequence gene secondary dysfunction their interaction partners retina. This review summarizes photoreceptor-RPE/MG supporting functions discusses how disruption these processes degeneration, an aim provide unique perspective pathogenesis paradigm. We will first describe biology then discuss between MG/RPE well implications disease pathogenesis. Finally, we summarize recent advances therapeutics targeting RPE.

Language: Английский

Citations

4