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Artikel ; Online: X-Linked Retinoschisis.

Ku, Cristy A / Wei, Lisa W / Sieving, Paul A

Cold Spring Harbor perspectives in medicine

2023 Band 13, Heft 9

Abstract: X-linked retinoschisis (XLRS) is an inherited vitreoretinal dystrophy causing visual impairment in males starting at a young age with an estimated prevalence of 1:5000 to 1:25,000. The condition was first observed in two affected brothers by Josef Haas ... ...

Abstract	X-linked retinoschisis (XLRS) is an inherited vitreoretinal dystrophy causing visual impairment in males starting at a young age with an estimated prevalence of 1:5000 to 1:25,000. The condition was first observed in two affected brothers by Josef Haas in 1898 and is clinically diagnosed by characteristic intraretinal cysts arranged in a petaloid "spoke-wheel" pattern centered in the macula. When clinical electroretinogram (ERG) testing began in the 1960s, XLRS was noted to have a characteristic reduction of the dark-adapted b-wave amplitude despite normal or usually nearly normal a-wave amplitudes, which became known as the "electronegative ERG response" of XLRS disease. The causative gene,
Mesh-Begriff(e)	Male ; Humans ; Animals ; Mice ; Retinoschisis/genetics ; Retinoschisis/therapy ; Retinoschisis/diagnosis ; Mutation ; Electroretinography ; Phenotype ; Genetic Therapy ; Eye Proteins/genetics ; Eye Proteins/metabolism ; Retina/metabolism
Chemische Substanzen	Eye Proteins
Sprache	Englisch
Erscheinungsdatum	2023-09-01
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ISSN	2157-1422
ISSN (online)	2157-1422
DOI	10.1101/cshperspect.a041288
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: X-linked Retinoschisis and Gene Therapy.

Mishra, Alaknanda / Sieving, Paul A

International ophthalmology clinics

2021 Band 61, Heft 4, Seite(n) 173–184

Mesh-Begriff(e)	Eye Proteins/genetics ; Genetic Therapy ; Humans ; Retinoschisis/genetics ; Retinoschisis/therapy ; Tomography, Optical Coherence
Chemische Substanzen	Eye Proteins
Sprache	Englisch
Erscheinungsdatum	2021-09-28
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	207382-1
ISSN	1536-9617 ; 0020-8167
ISSN (online)	1536-9617
ISSN	0020-8167
DOI	10.1097/IIO.0000000000000373
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Tissue engineering: NIH competition to create 'eye in a dish'.

Sieving, Paul A

Nature

2017 Band 546, Heft 7658, Seite(n) 352

Mesh-Begriff(e)	Humans ; Retina/physiology ; Tissue Engineering
Sprache	Englisch
Erscheinungsdatum	2017--14
Erscheinungsland	England
Dokumenttyp	Journal Article ; Comment
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/546352b
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Advances in understanding the molecular structure of retinoschisin while questions remain of biological function.

Heymann, J Bernard / Vijayasarathy, Camasamudram / Fariss, Robert N / Sieving, Paul A

Progress in retinal and eye research

2022 Band 95, Seite(n) 101147

Abstract: Retinoschisin (RS1) is a secreted protein that is essential for maintaining integrity of the retina. Numerous mutations in RS1 cause X-linked retinoschisis (XLRS), a progressive degeneration of the retina that leads to vision loss in young males. A key ... ...

Abstract	Retinoschisin (RS1) is a secreted protein that is essential for maintaining integrity of the retina. Numerous mutations in RS1 cause X-linked retinoschisis (XLRS), a progressive degeneration of the retina that leads to vision loss in young males. A key manifestation of XLRS is the formation of cavities (cysts) in the retina and separation of the layers (schisis), disrupting synaptic transmission. There are currently no approved treatments for patients with XLRS. Strategies using adeno-associated viral (AAV) vectors to deliver functional copies of RS1 as a form of gene augmentation therapy, are under clinical evaluation. To improve therapeutic strategies for treating XLRS, it is critical to better understand the secretion of RS1 and its molecular function. Immunofluorescence and immunoelectron microscopy show that RS1 is located on the surfaces of the photoreceptor inner segments and bipolar cells. Sequence homology indicates a discoidin domain fold, similar to many other proteins with demonstrated adhesion functions. Recent structural studies revealed the tertiary structure of RS1 as two back-to-back octameric rings, each cross-linked by disulfides. The observation of higher order structures in vitro suggests the formation of an adhesive matrix spanning the distance between cells (∼100 nm). Several studies indicated that RS1 readily binds to other proteins such as the sodium-potassium ATPase (NaK-ATPase) and extracellular matrix proteins. Alternatively, RS1 may influence fluid regulation via interaction with membrane proteins such as the NaK-ATPase, largely inferred from the use of carbonic anhydrase inhibitors to shrink the typical intra-retinal cysts in XLRS. We discuss these models in light of RS1 structure and address the difficulty in understanding the function of RS1.
Mesh-Begriff(e)	Male ; Humans ; Molecular Structure ; Retina/metabolism ; Retinoschisis/genetics ; Retinoschisis/metabolism ; Mutation ; Adenosine Triphosphatases/genetics ; Adenosine Triphosphatases/metabolism ; Eye Proteins/genetics
Chemische Substanzen	Adenosine Triphosphatases (EC 3.6.1.-) ; Eye Proteins
Sprache	Englisch
Erscheinungsdatum	2022-11-16
Erscheinungsland	England
Dokumenttyp	Journal Article ; Review
ZDB-ID	1182683-6
ISSN	1873-1635 ; 1350-9462
ISSN (online)	1873-1635
ISSN	1350-9462
DOI	10.1016/j.preteyeres.2022.101147
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Statistical Evaluation of ERG Responses: A New Method to Validate Cycle-by-Cycle Recordings in Advanced Retinal Degenerations.

Fadda, Antonello / Martelli, Francesco / Zein, Wadih M / Jeffrey, Brett / Placidi, Giorgio / Sieving, Paul A / Falsini, Benedetto

Investigative ophthalmology & visual science

2024 Band 65, Heft 4, Seite(n) 3

Abstract: Purpose: To describe and evaluate a novel method to determine the validity of measurements made using cycle-by-cycle (CxC) recording techniques in patients with advanced retinal degenerations (RD) having low-amplitude flicker electroretinogram (ERG) ... ...

Abstract	Purpose: To describe and evaluate a novel method to determine the validity of measurements made using cycle-by-cycle (CxC) recording techniques in patients with advanced retinal degenerations (RD) having low-amplitude flicker electroretinogram (ERG) responses. Methods: The method extends the original CxC recording algorithm introduced by Sieving et al., retaining the original recording setup and the preliminary analysis of raw data. Novel features include extended use of spectrum analysis, reduction of errors due to known sources, and a comprehensive statistical assessment using three different tests. The method was applied to ERG recordings from seven patients with RD and two patients with CNGB3 achromatopsia. Results: The method was implemented as a Windows application to processes raw data obtained from a commercial ERG system, and it features a computational toolkit for statistical assessment of ERG recordings with amplitudes as low as 1 µV, commonly found in advanced RD patients. When recorded using conditions specific for eliciting cone responses, none of the CNGB3 patients had a CxC validated response, indicating that no signal artifacts were present with our recording conditions. A comparison of the presented method with conventional 30 Hz ERG was performed. Bland-Altman plots indicated good agreement (mean difference, -0.045 µV; limits of agreement, 0.193 to -0.282 µV) between the resulting amplitudes. Within-session test-retest variability was 15%, comparing favorably to the variability of standard ERG amplitudes. Conclusions: This novel method extracts highly reliable clinical recordings of low-amplitude flicker ERGs and effectively detects artifactual responses. It has potential value both as a cone outcome variable and planning tool in clinical trials on natural history and treatment of advanced RDs.
Mesh-Begriff(e)	Humans ; Electroretinography/methods ; Retinal Degeneration/diagnosis ; Retinal Cone Photoreceptor Cells/physiology ; Color Vision Defects ; Photic Stimulation ; Retina/physiology
Sprache	Englisch
Erscheinungsdatum	2024-03-14
Erscheinungsland	United States
Dokumenttyp	Journal Article
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.65.4.3
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Of men and mice: Human X-linked retinoschisis and fidelity in mouse modeling.

Vijayasarathy, Camasamudram / Sardar Pasha, Sheik Pran Babu / Sieving, Paul A

Progress in retinal and eye research

2021 Band 87, Seite(n) 100999

Abstract: X-linked Retinoschisis (XLRS) is an early-onset transretinal dystrophy, often with a prominent macular component, that affects males and generally spares heterozygous females because of X-linked recessive inheritance. It results from loss-of-function RS1 ...

Abstract	X-linked Retinoschisis (XLRS) is an early-onset transretinal dystrophy, often with a prominent macular component, that affects males and generally spares heterozygous females because of X-linked recessive inheritance. It results from loss-of-function RS1 gene mutations on the X-chromosome. XLRS causes bilateral reduced acuities from young age, and on clinical exam and by ocular coherence tomography (OCT) the neurosensory retina shows foveo-macular cystic schisis cavities in the outer plexiform (OPL) and inner nuclear layers (INL). XLRS manifests between infancy and school-age with variable phenotypic presentation and without reliable genotype-phenotype correlations. INL disorganization disrupts synaptic signal transmission from photoreceptors to ON-bipolar cells, and this reduces the electroretinogram (ERG) bipolar b-wave disproportionately to photoreceptor a-wave changes. RS1 gene expression is localized mainly to photoreceptors and INL bipolar neurons, and RS1 protein is thought to play a critical cell adhesion role during normal retinal development and later for maintenance of retinal structure. Several independent XLRS mouse models with mutant RS1 were created that recapitulate features of human XLRS disease, with OPL-INL schisis cavities, early onset and variable phenotype across mutant models, and reduced ERG b-wave to a-wave amplitude ratio. The faithful phenotype of the XLRS mouse has assisted in delineating the disease pathophysiology. Delivery to XLRS mouse retina of an AAV8-RS1 construct under control of the RS1 promoter restores the retinal structure and synaptic function (with increase of b-wave amplitude). It also ameliorates the schisis-induced inflammatory microglia phenotype toward a state of immune quiescence. The results imply that XLRS gene therapy could yield therapeutic benefit to preserve morphological and functional retina particularly when intervention is conducted at earlier ages before retinal degeneration becomes irreversible. A phase I/IIa single-center, open-label, three-dose-escalation clinical trial reported a suitable safety and tolerability profile of intravitreally administered AAV8-RS1 gene replacement therapy for XLRS participants. Dose-related ocular inflammation occurred after dosing, but this resolved with topical and oral corticosteroids. Systemic antibodies against AAV8 increased in dose-dependent fashion, but no antibodies were observed against the RS1 protein. Retinal cavities closed transiently in one participant. Technological innovations in methods of gene delivery and strategies to further reduce immune responses are expected to enhance the therapeutic efficacy of the vector and ultimate success of a gene therapy approach.
Mesh-Begriff(e)	Animals ; Electroretinography ; Eye Proteins/genetics ; Eye Proteins/metabolism ; Female ; Genetic Therapy/methods ; Humans ; Male ; Mice ; Retina/metabolism ; Retinoschisis/genetics ; Retinoschisis/therapy
Chemische Substanzen	Eye Proteins
Sprache	Englisch
Erscheinungsdatum	2021-08-11
Erscheinungsland	England
Dokumenttyp	Journal Article ; Review
ZDB-ID	1182683-6
ISSN	1873-1635 ; 1350-9462
ISSN (online)	1873-1635
ISSN	1350-9462
DOI	10.1016/j.preteyeres.2021.100999
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: NEI audacious goals initiative to catalyze innovation.

Sieving, Paul A

Investigative ophthalmology & visual science

2012 Band 53, Heft 11, Seite(n) 7149–7150

Mesh-Begriff(e)	Biomedical Research/trends ; Delivery of Health Care, Integrated/trends ; Forecasting ; Health Promotion/trends ; Humans ; National Eye Institute (U.S.)/organization & administration ; Organizational Innovation ; Patient Care Planning/trends ; Patient-Centered Care/trends ; Quality of Health Care ; United States
Sprache	Englisch
Erscheinungsdatum	2012-10
Erscheinungsland	United States
Dokumenttyp	Editorial
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.12-11069
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: OCT Intensity of the Region between Outer Retina Band 2 and Band 3 as a Biomarker for Retinal Degeneration and Therapy.

Zeng, Yong / Gao, Shasha / Li, Yichao / Marangoni, Dario / De Silva, Tharindu / Wong, Wai T / Chew, Emily Y / Sun, Xun / Li, Tiansen / Sieving, Paul A / Qian, Haohua

Bioengineering (Basel, Switzerland)

2024 Band 11, Heft 5

Abstract: Optical coherence tomography (OCT) is widely used to probe retinal structure and function. This study investigated the outer retina band (ORB) pattern and reflective intensity for the region between bands 2 and 3 (Dip) in three mouse models of inherited ... ...

Abstract	Optical coherence tomography (OCT) is widely used to probe retinal structure and function. This study investigated the outer retina band (ORB) pattern and reflective intensity for the region between bands 2 and 3 (Dip) in three mouse models of inherited retinal degeneration (Rs1KO, TTLL5KO, RPE65KO) and in human AMD patients from the A2A database. OCT images were manually graded, and reflectivity signals were used to calculate the Dip ratio. Qualitative analyses demonstrated the progressive merging band 2 and band 3 in all three mouse models, leading to a reduction in the Dip ratio compared to wildtype (WT) controls. Gene replacement therapy in Rs1KO mice reverted the ORB pattern to one resembling WT and increased the Dip ratio. The degree of anatomical rescue in these mice was highly correlated with level of transgenic RS1 expression and with the restoration of ERG b-wave amplitudes. While the inner retinal cavity was significantly enlarged in dark-adapted Rs1KO mice, the Dip ratio was not altered. A reduction of the Dip ratio was also detected in AMD patients compared with healthy controls and was also positively correlated with AMD severity on the AMD score. We propose that the ORB and Dip ratio can be used as non-invasive early biomarkers for retina health, which can be used to probe therapeutic gene expression and to evaluate the effectiveness of therapy.
Sprache	Englisch
Erscheinungsdatum	2024-05-01
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article
ZDB-ID	2746191-9
ISSN	2306-5354
ISSN	2306-5354
DOI	10.3390/bioengineering11050449
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: MASSIVE ADVANCING NONEXUDATIVE TYPE 1 CHOROIDAL NEOVASCULARIZATION IN CTRP5 LATE-ONSET RETINAL DEGENERATION: Longitudinal Findings on Multimodal Imaging and Implications for Age-Related Macular Degeneration.

Keenan, Tiarnan D L / Vanderford, Elliott K / de Silva, Tharindu / Sieving, Paul A / Cukras, Catherine A

Retina (Philadelphia, Pa.)

2021 Band 41, Heft 11, Seite(n) 2236–2245

Abstract: Purpose: To describe longitudinal multimodal imaging findings of nonexudative choroidal neovascularization in CTRP5 late-onset retinal degeneration.: Methods: Four patients with CTRP5-positive late-onset retinal degeneration underwent repeated ... ...

Abstract	Purpose: To describe longitudinal multimodal imaging findings of nonexudative choroidal neovascularization in CTRP5 late-onset retinal degeneration. Methods: Four patients with CTRP5-positive late-onset retinal degeneration underwent repeated ophthalmoscopic examination and multimodal imaging. All four patients (two siblings and their cousins, from a pedigree described previously) had the heterozygous S163R mutation. Results: All four patients demonstrated large subretinal lesions in the mid-peripheral retina of both eyes. The lesions were characterized by confluent hypercyanescence with hypocyanescent borders on indocyanine green angiography, faintly visible branching vascular networks with absent/minimal leakage on fluorescein angiography, Type 1 neovascularization on optical coherence tomography angiography, and absent retinal fluid, consistent with nonexudative choroidal neovascularization. The neovascular membranes enlarged substantially over time and the birth of new membranes was observed, but all lesions remained nonexudative/minimally exudative. Without treatment, all involved retinal areas remained free of atrophy and subretinal fibrosis. Conclusion: We report the existence of massive advancing nonexudative Type 1 choroidal neovascularization in CTRP5 late-onset retinal degeneration. These findings have implications for age-related macular degeneration. They provide a monogenic model system for studying the mechanisms underlying the distinct events of choroidal neovascularization development, enlargement, progression to exudation, and atrophy in age-related macular degeneration. They suggest that choroidal hypoperfusion precedes neovascularization and that nonexudative neovascularization may protect against atrophy.
Mesh-Begriff(e)	Choroid/blood supply ; Choroid/diagnostic imaging ; Choroidal Neovascularization/diagnosis ; Choroidal Neovascularization/etiology ; Collagen/genetics ; Collagen/metabolism ; DNA Mutational Analysis ; Female ; Fluorescein Angiography/methods ; Fundus Oculi ; Humans ; Male ; Middle Aged ; Multimodal Imaging ; Mutation ; Retinal Degeneration/complications ; Retinal Degeneration/diagnosis ; Retinal Degeneration/genetics ; Severity of Illness Index ; Tomography, Optical Coherence/methods ; Visual Acuity
Chemische Substanzen	C1QTNF5 protein, human ; Collagen (9007-34-5)
Sprache	Englisch
Erscheinungsdatum	2021-05-14
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Observational Study
ZDB-ID	603192-4
ISSN	1539-2864 ; 0275-004X
ISSN (online)	1539-2864
ISSN	0275-004X
DOI	10.1097/IAE.0000000000003205
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Rs1h

Zeng, Yong / Qian, Haohua / Campos, Maria Mercedes / Li, Yichao / Vijayasarathy, Camasamudram / Sieving, Paul A

Gene therapy

2021 Band 29, Heft 7-8, Seite(n) 431–440

Abstract: Animal models of X-linked juvenile retinoschisis (XLRS) are valuable tools for understanding basic biochemical function of retinoschisin (RS1) protein and to investigate outcomes of preclinical efficacy and toxicity studies. In order to work with an eye ... ...

Abstract	Animal models of X-linked juvenile retinoschisis (XLRS) are valuable tools for understanding basic biochemical function of retinoschisin (RS1) protein and to investigate outcomes of preclinical efficacy and toxicity studies. In order to work with an eye larger than mouse, we generated and characterized an Rs1h
Mesh-Begriff(e)	Animals ; Cell Adhesion Molecules/genetics ; Dietary Supplements ; Electroretinography ; Exons/genetics ; Eye Proteins/genetics ; Eye Proteins/metabolism ; Humans ; Phenotype ; Rats ; Retina/metabolism ; Retinoschisis/genetics ; Retinoschisis/pathology ; Retinoschisis/therapy
Chemische Substanzen	Cell Adhesion Molecules ; Eye Proteins ; RS1 protein, human
Sprache	Englisch
Erscheinungsdatum	2021-09-22
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, N.I.H., Extramural
ZDB-ID	1191036-7
ISSN	1476-5462 ; 0969-7128
ISSN (online)	1476-5462
ISSN	0969-7128
DOI	10.1038/s41434-021-00290-6
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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