Generation of the induced pluripotent stem cell line from a patient with autosomal recessive ABCA4-mediated Stargardt Macular Dystrophy

Claassen, Johann; Zhang, Dan; Chen, Shang-Chih; Moon, Sang Yoon; Lamey, Tina M.; Thompson, Jennifer A.; McLaren, Terri L.; Roach, John N. De; McLenachan, Samuel; Chen, Fred K.

doi:10.1016/j.scr.2018.11.013

Cited by 8 publications

(7 citation statements)

References 4 publications

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“…40 Various iPSC lines have been generated to represent the myriad of ABCA4 mutations seen in STGD1. 41,42 Using iPSCderived tissue to model a disease such as STGD1 is useful in attempts to link causality and severity with expression levels, since patient lines retain the complex genetic signatures created via natural splicing and editing that occurs in vivo. In one study, eight iPSC lines from patients harbouring a single pathogenic ABCA4 variant and normal controls were differentiated into RPE and subjected to RNA equencing and protein analysis.…”

Section: Stargardt Diseasementioning

confidence: 99%

“…ABCA4 displays extensive allelic heterogeneity with over 1000 pathogenic variants to date 40 . Various iPSC lines have been generated to represent the myriad of ABCA4 mutations seen in STGD1 41,42 . Using iPSC‐derived tissue to model a disease such as STGD1 is useful in attempts to link causality and severity with expression levels, since patient lines retain the complex genetic signatures created via natural splicing and editing that occurs in vivo.…”

Section: Modelling Inherited Retinal Diseasementioning

confidence: 99%

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Human pluripotent stem cells for the modelling of retinal pigment epithelium homeostasis and disease: A review

Hall

Paull

Pébay

et al. 2022

Clinical Exper Ophthalmology

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Human pluripotent stem cells (hPSCs), which include induced pluripotent stem cells and embryonic stem cells, are powerful tools for studying human development, physiology and disease, including those affecting the retina. Cells from selected individuals, or specific genetic backgrounds, can be differentiated into distinct cell types allowing the modelling of diseases in a dish for therapeutic development. hPSC-derived retinal cultures have already been used to successfully model retinal pigment epithelium (RPE) degeneration for various retinal diseases including monogenic conditions and complex disease such as age-related macular degeneration. Here, we will review the current knowledge gained in understanding the molecular events involved in retinal disease using hPSC-derived retinal models, in particular RPE models. We will provide examples of various conditions to illustrate the scope of applications associated with the use of hPSC-derived RPE models.

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Section: Stargardt Diseasementioning

confidence: 99%

Section: Modelling Inherited Retinal Diseasementioning

confidence: 99%

Human pluripotent stem cells for the modelling of retinal pigment epithelium homeostasis and disease: A review

Hall

Paull

Pébay

et al. 2022

Clinical Exper Ophthalmology

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“…The generation of induced pluripotent stem cell (iPSC)-derived photoreceptor cells would be of great use to STGD1, STGD3 and STGD4 studies but this can be relatively technical [40]. Generating iPSCs can take 20-30 days, with the subsequent differentiation into retinal photoreceptor-like cells requiring a further 10-14 days of specialised culture conditions.…”

Section: In Vitro Modelsmentioning

confidence: 99%

Therapy Approaches for Stargardt Disease

2021

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Despite being the most prevalent cause of inherited blindness in children, Stargardt disease is yet to achieve the same clinical trial success as has been achieved for other inherited retinal diseases. With an early age of onset and continual progression of disease over the life course of an individual, Stargardt disease appears to lend itself to therapeutic intervention. However, the aetiology provides issues not encountered with the likes of choroideremia and X-linked retinitis pigmentosa and this has led to a spectrum of treatment strategies that approach the problem from different aspects. These include therapeutics ranging from small molecules and anti-sense oligonucleotides to viral gene supplementation and cell replacement. The advancing development of CRISPR-based molecular tools is also likely to contribute to future therapies by way of genome editing. In this we review, we consider the most recent pre-clinical and clinical trial data relating to the different strategies being applied to the problem of generating a treatment for the large cohort of Stargardt disease patients worldwide.

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“…Although the effects of ABCA4 splice-site variants have been evaluated in in vitro assays [16,24,[26][27][28][29][30], these may not always mimic splice defects in vivo [24]. The analysis of deep intronic variants with induced pluripotent stem cell-derived photoreceptor cells (iPSC-derived PCs) is an even more tedious task [27,[31][32][33]. Therefore, novel methods for assessment of ABCA4 gene mutations are highly desirable.…”

Section: Introductionmentioning

confidence: 99%

“…Analysis of RNA isolated from cultured human keratinocytes or dermal fibroblasts has revealed ABCA4 transcript alterations caused by splice-site mutations located mainly in the introns of the latter half of the ABCA4 gene [16,23,26,27,29,31,33,38]. It has been reported that normal human keratinocytes express an alternatively spliced truncated 70 kDa isoform of ABCA4 [36].…”

Section: Introductionmentioning

confidence: 99%

Molecular Analysis of the ABCA4 Gene Mutations in Patients with Stargardt Disease Using Human Hair Follicles

Ścieżyńska

Soszyńska

Komorowski

et al. 2020

IJMS

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ABCA4 gene mutations are the cause of a spectrum of ABCA4 retinopathies, and the most common juvenile macular degeneration is called Stargardt disease. ABCA4 has previously been observed almost exclusively in the retina. Therefore, studying the functional consequences of ABCA4 variants has required advanced molecular analysis techniques. The aim of the present study was to evaluate whether human hair follicles may be used for molecular analysis of the ABCA4 gene splice-site variants in patients with ABCA4 retinopathies. We assessed ABCA4 expression in hair follicles and skin at mRNA and protein levels by means of real-time PCR and Western blot analyses, respectively. We performed cDNA sequencing to reveal the presence of full-length ABCA4 transcripts and analyzed ABCA4 transcripts from three patients with Stargardt disease carrying different splice-site ABCA4 variants: c.5312+1G>A, c.5312+2T>G and c.5836-3C>A. cDNA analysis revealed that c.5312+1G>A, c.5312+2T>G variants led to the skipping of exon 37, and the c.5836-3C>A variant resulted in the insertion of 30 nucleotides into the transcript. Our results strongly argue for the use of hair follicles as a model for the molecular analysis of the pathogenicity of ABCA4 variants in patients with ABCA4 retinopathies.

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Generation of the induced pluripotent stem cell line from a patient with autosomal recessive ABCA4-mediated Stargardt Macular Dystrophy

Cited by 8 publications

References 4 publications

Human pluripotent stem cells for the modelling of retinal pigment epithelium homeostasis and disease: A review

Human pluripotent stem cells for the modelling of retinal pigment epithelium homeostasis and disease: A review

Therapy Approaches for Stargardt Disease

Molecular Analysis of the ABCA4 Gene Mutations in Patients with Stargardt Disease Using Human Hair Follicles

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