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

Abstract

Introduction: Friedreich’s ataxia (FRDA) is an autosomal recessive multisystem disease mainly affecting the peripheral and central nervous systems, and heart. FRDA is caused by a GAA repeat expansion in the first intron of the frataxin (FXN) gene, that leads to reduced expression of FXN mRNA and frataxin protein. Neuronal and cardiac cells are primary targets of frataxin deficiency and generating models via differentiation of induced pluripotent stem cells (iPSCs) into these cell types is essential for progress towards developing therapies for FRDA. Areas covered: This review is focused on modeling FRDA using human iPSCs and various iPSC-differentiated cell types. We emphasized the importance of patient and corrected isogenic cell line pairs to minimize effects caused by biological variability between individuals. Expert opinion: The versatility of iPSC-derived cellular models of FRDA is advantageous for developing new therapeutic strategies, and rigorous testing in such models will be critical for approval of the first treatment for FRDA. Creating a well-characterized and diverse set of iPSC lines, including appropriate isogenic controls, will facilitate achieving this goal. Also, improvement of differentiation protocols, especially towards proprioceptive sensory neurons and organoid generation, is necessary to utilize the full potential of iPSC technology in the drug discovery process.

Perspectives on current models of Friedreich’s ataxia

“…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 ).…”

“…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 ).…”

“…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.…”

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

“…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 ).…”

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

“…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.…”