Progress in understanding Friedreich’s ataxia using human induced pluripotent stem cells

Schreiber, Anna M.; Misiorek, Julia O.; Napierala, Marek; Напиерала, Марек

doi:10.1080/21678707.2019.1562334

Cited by 7 publications

(6 citation statements)

References 94 publications

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“…Decrease in frataxin expression causes iron accumulation, impaired iron–sulfur cluster biogenesis, increased oxidative stress, mitochondrial dysfunctioning (Calap-Quintana et al, 2018; Gonzalez-Cabo & Palau, 2013 ; Santos et al, 2010 ), and ferroptosis ( Cotticelli et al, 2019 ; La Rosa et al, 2020 ; Turchi et al, 2020 ; Terzi et al, 2021 ). These phenotypes were also recapitulated in iPSC-based in vitro models of FRDA ( Schreiber et al, 2019 ). Here, we highlight recent studies utilizing FRDA iPSC-based models ( Table 1 ).…”

Section: Generation Of Patient-specific Induced Pluripotent Stem Cellsmentioning

confidence: 91%

“…FXN downregulation observed in fibroblasts was found to be retained in the iPSCs ( Ku et al, 2010 ). Since then, several additional FRDA patient-derived iPSCs were generated to study the pathophysiology of this disease ( Liu et al, 2011 ; Bolotta et al, 2019 ; Schreiber et al, 2019 ; Dionisi et al, 2020 ; Mazzara et al, 2020 ; Angulo et al, 2021 ; Kelekci et al, 2021 ).…”

Section: Generation Of Patient-specific Induced Pluripotent Stem Cellsmentioning

confidence: 99%

“…In vivo models of FRDA include yeast, nematode worm, fruit fly, and mice ( Babcock et al, 1997 ; Radisky et al, 1999 ; Puccio et al, 2001 ; Al-Mahdawi et al, 2004 ; Vázquez-Manrique et al, 2006 ; Virmouni et al, 2014 ; Monnier et al, 2018 ), whereas FRDA in vitro models include patient-derived cells such as immortalized lymphoblastoid cells, primary fibroblasts ( Li et al, 2016 ; Agro and Diaz-Nido, 2020 ; Misiorek et al, 2020 ; Johnson et al, 2021 ), FRDA-derived iPSCs ( Angulo et al, 2021 ; Kelekci et al, 2021 ), and iPSC-based models such as neurons, cardiomyocytes, and beta cells ( Crombie et al, 2016 ; Schreiber et al, 2019 ) ( Figure 1 ). All these FRDA models need to imitate the symptoms of FRDA patients.…”

Section: Introductionmentioning

confidence: 99%

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Perspectives on current models of Friedreich’s ataxia

Kelekçi

Yıldız

Sevinç

et al. 2022

Front. Cell Dev. Biol.

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Friedreich’s ataxia (FRDA, OMIM#229300) is the most common hereditary ataxia, resulting from the reduction of frataxin protein levels due to the expansion of GAA repeats in the first intron of the FXN gene. Why the triplet repeat expansion causes a decrease in Frataxin protein levels is not entirely known. Generation of effective FRDA disease models is crucial for answering questions regarding the pathophysiology of this disease. There have been considerable efforts to generate in vitro and in vivo models of FRDA. In this perspective article, we highlight studies conducted using FRDA animal models, patient-derived materials, and particularly induced pluripotent stem cell (iPSC)-derived models. We discuss the current challenges in using FRDA animal models and patient-derived cells. Additionally, we provide a brief overview of how iPSC-based models of FRDA were used to investigate the main pathways involved in disease progression and to screen for potential therapeutic agents for FRDA. The specific focus of this perspective article is to discuss the outlook and the remaining challenges in the context of FRDA iPSC-based models.

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Section: Generation Of Patient-specific Induced Pluripotent Stem Cellsmentioning

confidence: 91%

Section: Generation Of Patient-specific Induced Pluripotent Stem Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Perspectives on current models of Friedreich’s ataxia

Kelekçi

Yıldız

Sevinç

et al. 2022

Front. Cell Dev. Biol.

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“…For example, in neurological diseases caused by triplet repeat expansions such as Friedrich ataxia (FA) there is significant clinical heterogeneity. This can be due to both gene-dependent factors such as expansion size and gene-independent factors such as genetic background and environmental factors (Schreiber et al, 2019 ). Therefore, isogenic controls were necessary to discriminate truly FRDA -intrinsic effects, with restoration of frataxin expression and other FA phenotypic features in response to ZFN excision of the expanded GAA repeat (Li Y. et al, 2015 ).…”

Section: Deriving Neuronal Systems From Ipscmentioning

confidence: 99%

Genome Editing in iPSC-Based Neural Systems: From Disease Models to Future Therapeutic Strategies

et al. 2021

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Therapeutic advances for neurological disorders are challenging due to limited accessibility of the human central nervous system and incomplete understanding of disease mechanisms. Many neurological diseases lack precision treatments, leading to significant disease burden and poor outcome for affected patients. Induced pluripotent stem cell (iPSC) technology provides human neuronal cells that facilitate disease modeling and development of therapies. The use of genome editing, in particular CRISPR-Cas9 technology, has extended the potential of iPSCs, generating new models for a number of disorders, including Alzheimers and Parkinson Disease. Editing of iPSCs, in particular with CRISPR-Cas9, allows generation of isogenic pairs, which differ only in the disease-causing mutation and share the same genetic background, for assessment of phenotypic differences and downstream effects. Moreover, genome-wide CRISPR screens allow high-throughput interrogation for genetic modifiers in neuronal phenotypes, leading to discovery of novel pathways, and identification of new therapeutic targets. CRISPR-Cas9 has now evolved beyond altering gene expression. Indeed, fusion of a defective Cas9 (dCas9) nuclease with transcriptional repressors or activation domains allows down-regulation or activation of gene expression (CRISPR interference, CRISPRi; CRISPR activation, CRISPRa). These new tools will improve disease modeling and facilitate CRISPR and cell-based therapies, as seen for epilepsy and Duchenne muscular dystrophy. Genome engineering holds huge promise for the future understanding and treatment of neurological disorders, but there are numerous barriers to overcome. The synergy of iPSC-based model systems and gene editing will play a vital role in the route to precision medicine and the clinical translation of genome editing-based therapies.

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“…We have focused on mitochondrial diseases for which multiple hPSC cell lines have been reported, with similar findings uncovered from the various publications. We have elected to exclude the extensive studies involving hPSC models of Friedreich’s ataxia, caused by GAA triplet-repeat expansions in FXN , which have been reviewed elsewhere [ 106 ]. See Table A3 and Table A4 for details regarding cell lines, controls, and functional outcomes from these hPSC-derived mitochondrial disease models, and others not specifically featured below.…”

Section: Functional Studiesmentioning

confidence: 99%

Modelling Mitochondrial Disease in Human Pluripotent Stem Cells: What Have We Learned?

McKnight

Low

Elliott

et al. 2021

IJMS

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Mitochondrial diseases disrupt cellular energy production and are among the most complex group of inherited genetic disorders. Affecting approximately 1 in 5000 live births, they are both clinically and genetically heterogeneous, and can be highly tissue specific, but most often affect cell types with high energy demands in the brain, heart, and kidneys. There are currently no clinically validated treatment options available, despite several agents showing therapeutic promise. However, modelling these disorders is challenging as many non-human models of mitochondrial disease do not completely recapitulate human phenotypes for known disease genes. Additionally, access to disease-relevant cell or tissue types from patients is often limited. To overcome these difficulties, many groups have turned to human pluripotent stem cells (hPSCs) to model mitochondrial disease for both nuclear-DNA (nDNA) and mitochondrial-DNA (mtDNA) contexts. Leveraging the capacity of hPSCs to differentiate into clinically relevant cell types, these models permit both detailed investigation of cellular pathomechanisms and validation of promising treatment options. Here we catalogue hPSC models of mitochondrial disease that have been generated to date, summarise approaches and key outcomes of phenotypic profiling using these models, and discuss key criteria to guide future investigations using hPSC models of mitochondrial disease.

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Progress in understanding Friedreich’s ataxia using human induced pluripotent stem cells

Cited by 7 publications

References 94 publications

Perspectives on current models of Friedreich’s ataxia

Perspectives on current models of Friedreich’s ataxia

Genome Editing in iPSC-Based Neural Systems: From Disease Models to Future Therapeutic Strategies

Modelling Mitochondrial Disease in Human Pluripotent Stem Cells: What Have We Learned?

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