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Article ; Online: Eye on a Dish Models to Evaluate Splicing Modulation.

Hau, Kwan-Leong / Lane, Amelia / Guarascio, Rosellina / Cheetham, Michael E

Methods in molecular biology (Clifton, N.J.)

2022 Volume 2434, Page(s) 245–255

Abstract: Inherited retinal dystrophies, such as Leber congenital amaurosis, Stargardt disease, and retinitis pigmentosa, are characterized by photoreceptor dysfunction and death and currently have few treatment options. Recent technological advances in induced ... ...

Abstract	Inherited retinal dystrophies, such as Leber congenital amaurosis, Stargardt disease, and retinitis pigmentosa, are characterized by photoreceptor dysfunction and death and currently have few treatment options. Recent technological advances in induced pluripotent stem cell (iPSC) technology and differentiation methods mean that human photoreceptors can now be studied in vitro. For example, retinal organoids provide a platform to study the development of the human retina and mechanisms of diseases in the dish, as well as being a potential source for cell transplantation. Here, we describe differentiation protocols for 3D cultures that produce retinal organoids containing photoreceptors with rudimentary outer segments. These protocols can be used as a model to understand retinal disease mechanisms and test potential therapies, including antisense oligonucleotides (AONs) to alter gene expression or RNA processing. This "retina in a dish" model is well suited for use with AONs, as the organoids recapitulate patient mutations in the correct genomic and cellular context, to test potential efficacy and examine off-target effects on the translational path to the clinic.
MeSH term(s)	Cell Differentiation/genetics ; Humans ; Induced Pluripotent Stem Cells ; Organoids ; Photoreceptor Cells ; Retina/metabolism ; Retinitis Pigmentosa/metabolism
Language	English
Publishing date	2022-02-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-2010-6_16
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Article ; Online: Pluripotent stem cell-derived models of retinal disease: Elucidating pathogenesis, evaluating novel treatments, and estimating toxicity.

Kurzawa-Akanbi, Marzena / Tzoumas, Nikolaos / Corral-Serrano, Julio C / Guarascio, Rosellina / Steel, David H / Cheetham, Michael E / Armstrong, Lyle / Lako, Majlinda

Progress in retinal and eye research

2024 Volume 100, Page(s) 101248

Abstract: Blindness poses a growing global challenge, with approximately 26% of cases attributed to degenerative retinal diseases. While gene therapy, optogenetic tools, photosensitive switches, and retinal prostheses offer hope for vision restoration, these high- ... ...

Abstract	Blindness poses a growing global challenge, with approximately 26% of cases attributed to degenerative retinal diseases. While gene therapy, optogenetic tools, photosensitive switches, and retinal prostheses offer hope for vision restoration, these high-cost therapies will benefit few patients. Understanding retinal diseases is therefore key to advance effective treatments, requiring in vitro models replicating pathology and allowing quantitative assessments for drug discovery. Pluripotent stem cells (PSCs) provide a unique solution given their limitless supply and ability to differentiate into light-responsive retinal tissues encompassing all cell types. This review focuses on the history and current state of photoreceptor and retinal pigment epithelium (RPE) cell generation from PSCs. We explore the applications of this technology in disease modelling, experimental therapy testing, biomarker identification, and toxicity studies. We consider challenges in scalability, standardisation, and reproducibility, and stress the importance of incorporating vasculature and immune cells into retinal organoids. We advocate for high-throughput automation in data acquisition and analyses and underscore the value of advanced micro-physiological systems that fully capture the interactions between the neural retina, RPE, and choriocapillaris.
Language	English
Publishing date	2024-02-16
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1182683-6
ISSN	1873-1635 ; 1350-9462
ISSN (online)	1873-1635
ISSN	1350-9462
DOI	10.1016/j.preteyeres.2024.101248
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Article ; Online: A Proximity Complementation Assay to Identify Small Molecules That Enhance the Traffic of ABCA4 Misfolding Variants.

Piccolo, Davide / Zarouchlioti, Christina / Bellingham, James / Guarascio, Rosellina / Ziaka, Kalliopi / Molday, Robert S / Cheetham, Michael E

International journal of molecular sciences

2024 Volume 25, Issue 8

Abstract: ABCA4-related retinopathy is the most common inherited Mendelian eye disorder worldwide, caused by biallelic variants in the ATP-binding cassette transporter ABCA4. To date, over 2200 ABCA4 variants have been identified, including missense, nonsense, ... ...

Abstract	ABCA4-related retinopathy is the most common inherited Mendelian eye disorder worldwide, caused by biallelic variants in the ATP-binding cassette transporter ABCA4. To date, over 2200 ABCA4 variants have been identified, including missense, nonsense, indels, splice site and deep intronic defects. Notably, more than 60% are missense variants that can lead to protein misfolding, mistrafficking and degradation. Currently no approved therapies target ABCA4. In this study, we demonstrate that ABCA4 misfolding variants are temperature-sensitive and reduced temperature growth (30 °C) improves their traffic to the plasma membrane, suggesting the folding of these variants could be rescuable. Consequently, an in vitro platform was developed for the rapid and robust detection of ABCA4 traffic to the plasma membrane in transiently transfected cells. The system was used to assess selected candidate small molecules that were reported to improve the folding or traffic of other ABC transporters. Two candidates, 4-PBA and AICAR, were identified and validated for their ability to enhance both wild-type ABCA4 and variant trafficking to the cell surface in cell culture. We envision that this platform could serve as a primary screen for more sophisticated in vitro testing, enabling the discovery of breakthrough agents to rescue ABCA4 protein defects and mitigate ABCA4-related retinopathy.
MeSH term(s)	ATP-Binding Cassette Transporters/genetics ; ATP-Binding Cassette Transporters/metabolism ; Humans ; Protein Folding/drug effects ; Protein Transport ; HEK293 Cells ; Cell Membrane/metabolism ; Small Molecule Libraries/pharmacology
Chemical Substances	ATP-Binding Cassette Transporters ; ABCA4 protein, human ; Small Molecule Libraries
Language	English
Publishing date	2024-04-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25084521
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Article ; Online: Unpicking the UPR.

Cheetham, Michael E

Investigative ophthalmology & visual science

2012 Volume 53, Issue 11, Page(s) 7167

MeSH term(s)	Activating Transcription Factor 6/metabolism ; Endoplasmic Reticulum Stress/physiology ; Humans ; Retinitis Pigmentosa/metabolism ; Rhodopsin/metabolism ; Signal Transduction/physiology ; eIF-2 Kinase/metabolism
Chemical Substances	ATF6 protein, human ; Activating Transcription Factor 6 ; Rhodopsin (9009-81-8) ; PERK kinase (EC 2.7.11.1) ; eIF-2 Kinase (EC 2.7.11.1)
Language	English
Publishing date	2012-10-01
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.12-11004
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Article ; Online: Proof-of-concept for multiple AON delivery by a single U7snRNA vector to restore splicing defects in ABCA4.

Suárez-Herrera, Nuria / Riswick, Iris B / Vázquez-Domínguez, Irene / Duijkers, Lonneke / Karjosukarso, Dyah W / Piccolo, Davide / Bauwens, Miriam / De Baere, Elfride / Cheetham, Michael E / Garanto, Alejandro / Collin, Rob W J

Molecular therapy : the journal of the American Society of Gene Therapy

2024 Volume 32, Issue 3, Page(s) 837–851

Abstract: The high allelic heterogeneity in Stargardt disease (STGD1) complicates the design of intervention strategies. A significant proportion of pathogenic intronic ABCA4 variants alters the pre-mRNA splicing process. Antisense oligonucleotides (AONs) are an ... ...

Abstract	The high allelic heterogeneity in Stargardt disease (STGD1) complicates the design of intervention strategies. A significant proportion of pathogenic intronic ABCA4 variants alters the pre-mRNA splicing process. Antisense oligonucleotides (AONs) are an attractive yet mutation-specific therapeutic strategy to restore these splicing defects. In this study, we experimentally assessed the potential of a splicing modulation therapy to target multiple intronic ABCA4 variants. AONs were inserted into U7snRNA gene cassettes and tested in midigene-based splice assays. Five potent antisense sequences were selected to generate a multiple U7snRNA cassette construct, and this combination vector showed substantial rescue of all of the splicing defects. Therefore, the combination cassette was used for viral synthesis and assessment in patient-derived photoreceptor precursor cells (PPCs). Simultaneous delivery of several modified U7snRNAs through a single AAV, however, did not show substantial splicing correction, probably due to suboptimal transduction efficiency in PPCs and/or a heterogeneous viral population containing incomplete AAV genomes. Overall, these data demonstrate the potential of the U7snRNA system to rescue multiple splicing defects, but also suggest that AAV-associated challenges are still a limiting step, underscoring the need for further optimization before implementing this strategy as a potential treatment for STGD1.
MeSH term(s)	Humans ; ATP-Binding Cassette Transporters/genetics ; RNA Splicing ; Stargardt Disease/genetics ; Mutation ; Photoreceptor Cells
Chemical Substances	ATP-Binding Cassette Transporters ; ABCA4 protein, human
Language	English
Publishing date	2024-01-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	2010592-7
ISSN	1525-0024 ; 1525-0016
ISSN (online)	1525-0024
ISSN	1525-0016
DOI	10.1016/j.ymthe.2024.01.019
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Zs.A 5640: Show issues

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Article: Targeting the Proteostasis Network in Rhodopsin Retinitis Pigmentosa.

Parfitt, David A / Cheetham, Michael E

Advances in experimental medicine and biology

2016 Volume 854, Page(s) 479–484

Abstract: Mutations in rhodopsin are one of the most common causes of retinitis pigmentosa (RP). Misfolding of rhodopsin can result in disruptions in cellular protein homeostasis, or proteostasis. There is currently no available treatment for RP. In this review, ... ...

Abstract	Mutations in rhodopsin are one of the most common causes of retinitis pigmentosa (RP). Misfolding of rhodopsin can result in disruptions in cellular protein homeostasis, or proteostasis. There is currently no available treatment for RP. In this review, we discuss the different approaches currently being investigated for treatment of rhodopsin RP, focusing on the potential of manipulation of the proteostasis network as a therapeutic approach to combat retinal degeneration.
MeSH term(s)	Animals ; Disease Models, Animal ; Genetic Predisposition to Disease/genetics ; Humans ; Molecular Targeted Therapy/methods ; Mutation ; Proteostasis Deficiencies/drug therapy ; Proteostasis Deficiencies/genetics ; Retinaldehyde/therapeutic use ; Retinitis Pigmentosa/drug therapy ; Retinitis Pigmentosa/genetics ; Rhodopsin/chemistry ; Rhodopsin/genetics
Chemical Substances	Rhodopsin (9009-81-8) ; Retinaldehyde (RR725D715M)
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-319-17121-0_64
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Article ; Online: Induced Pluripotent Stem Cells for Inherited Optic Neuropathies-Disease Modeling and Therapeutic Development.

Harvey, Joshua Paul / Sladen, Paul Edward / Yu-Wai-Man, Patrick / Cheetham, Michael E

Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society

2021 Volume 42, Issue 1, Page(s) 35–44

Abstract: Background: Inherited optic neuropathies (IONs) cause progressive irreversible visual loss in children and young adults. There are limited disease-modifying treatments, and most patients progress to become severely visually impaired, fulfilling the ... ...

Abstract	Background: Inherited optic neuropathies (IONs) cause progressive irreversible visual loss in children and young adults. There are limited disease-modifying treatments, and most patients progress to become severely visually impaired, fulfilling the legal criteria for blind registration. The seminal discovery of the technique for reprogramming somatic nondividing cells into induced pluripotent stem cells (iPSCs) has opened several exciting opportunities in the field of ION research and treatment. Evidence acquisition: A systematic review of the literature was conducted with PubMed using the following search terms: autosomal dominant optic atrophy, ADOA, dominant optic atrophy, DOA, Leber hereditary optic neuropathy, LHON, optic atrophy, induced pluripotent stem cell, iPSC, iPSC derived, iPS, stem cell, retinal ganglion cell, and RGC. Clinical trials were identified on the ClinicalTrials.gov website. Results: This review article is focused on disease modeling and the therapeutic strategies being explored with iPSC technologies for the 2 most common IONs, namely, dominant optic atrophy and Leber hereditary optic neuropathy. The rationale and translational advances for cell-based and gene-based therapies are explored, as well as opportunities for neuroprotection and drug screening. Conclusions: iPSCs offer an elegant, patient-focused solution to the investigation of the genetic defects and disease mechanisms underpinning IONs. Furthermore, this group of disorders is uniquely amenable to both the disease modeling capability and the therapeutic potential that iPSCs offer. This fast-moving area will remain at the forefront of both basic and translational ION research in the coming years, with the potential to accelerate the development of effective therapies for patients affected with these blinding diseases.
MeSH term(s)	Child ; Humans ; Induced Pluripotent Stem Cells ; Ions ; Optic Atrophy, Autosomal Dominant/diagnosis ; Optic Atrophy, Autosomal Dominant/genetics ; Optic Atrophy, Autosomal Dominant/therapy ; Optic Atrophy, Hereditary, Leber/diagnosis ; Optic Atrophy, Hereditary, Leber/genetics ; Optic Atrophy, Hereditary, Leber/therapy ; Optic Nerve Diseases/genetics ; Optic Nerve Diseases/therapy ; Young Adult
Chemical Substances	Ions
Language	English
Publishing date	2021-09-30
Publishing country	United States
Document type	Journal Article ; Systematic Review
ZDB-ID	1189901-3
ISSN	1536-5166 ; 1070-8022
ISSN (online)	1536-5166
ISSN	1070-8022
DOI	10.1097/WNO.0000000000001375
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Article ; Online: Commentary: chaperoning against neuronal vulnerability (commentary on Zijlstra et al.).

Cheetham, Michael E

The European journal of neuroscience

2010 Volume 32, Issue 5, Page(s) 759

MeSH term(s)	Humans ; Molecular Chaperones/genetics ; Molecular Chaperones/physiology ; Nerve Degeneration/genetics ; Nerve Degeneration/physiopathology
Chemical Substances	Molecular Chaperones
Language	English
Publishing date	2010-10-11
Publishing country	France
Document type	Comment ; Journal Article
ZDB-ID	645180-9
ISSN	1460-9568 ; 0953-816X
ISSN (online)	1460-9568
ISSN	0953-816X
DOI	10.1111/j.1460-9568.2010.07388.x
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Article: Hsp90 as a Potential Therapeutic Target in Retinal Disease.

Aguilà, Mònica / Cheetham, Michael E

Advances in experimental medicine and biology

2015 Volume 854, Page(s) 161–167

Abstract: The molecular chaperone heat shock protein 90 (Hsp90) is a pivotal cellular regulator involved in the folding, activation and assembly of a wide range of proteins. Hsp90 has multiple roles in the retina and the use of different Hsp90 inhibitors has been ... ...

Abstract	The molecular chaperone heat shock protein 90 (Hsp90) is a pivotal cellular regulator involved in the folding, activation and assembly of a wide range of proteins. Hsp90 has multiple roles in the retina and the use of different Hsp90 inhibitors has been shown to prevent retinal degeneration in models of retinitis pigmentosa and age-related macular degeneration. Hsp90 is also a potential target in uveal melanoma. Mechanistically, Hsp90 inhibition can evoke a dual response in the retina; stimulating a stress response with molecular chaperone expression. Thereby leading to an improvement in visual function and photoreceptor survival; however, prolonged inhibition can also stimulate the degradation of Hsp90 client proteins potentially deleteriously affect vision. Here, we review the multiple roles of Hsp90 in the retina and the therapeutic potential of Hsp90 as a target.
MeSH term(s)	HSP90 Heat-Shock Proteins/antagonists & inhibitors ; HSP90 Heat-Shock Proteins/metabolism ; Humans ; Macular Degeneration/drug therapy ; Macular Degeneration/metabolism ; Molecular Chaperones/metabolism ; Molecular Targeted Therapy/methods ; Pyridones/therapeutic use ; Pyrimidines/therapeutic use ; Retina/drug effects ; Retina/metabolism ; Retina/pathology ; Retinal Diseases/drug therapy ; Retinal Diseases/metabolism ; Retinitis Pigmentosa/drug therapy ; Retinitis Pigmentosa/metabolism ; Vision, Ocular/drug effects
Chemical Substances	2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido(4,3-d)pyrimidin-5(6H)-one ; HSP90 Heat-Shock Proteins ; Molecular Chaperones ; Pyridones ; Pyrimidines
Language	English
Publishing date	2015-09-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-319-17121-0_22
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Article: CRISPR-Cas9 correction of a nonsense mutation in

Afanasyeva, Tess A V / Athanasiou, Dimitra / Perdigao, Pedro R L / Whiting, Kae R / Duijkers, Lonneke / Astuti, Galuh D N / Bennett, Jean / Garanto, Alejandro / van der Spuy, Jacqueline / Roepman, Ronald / Cheetham, Michael E / Collin, Rob W J

Molecular therapy. Methods & clinical development

2023 Volume 29, Page(s) 522–531

Abstract: Mutations in the lebercilin-encoding ... ...

Abstract	Mutations in the lebercilin-encoding gene
Language	English
Publishing date	2023-05-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	2872938-9
ISSN	2329-0501 ; 2329-0501
ISSN (online)	2329-0501
ISSN	2329-0501
DOI	10.1016/j.omtm.2023.05.012
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