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 the 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.

KEYWORDS:

• Induced pluripotent stem cells
• frataxin
• Friedreich’s ataxia
• GAA repeat expansion
• differentiation

Article highlights

• Friedreich’s ataxia (FRDA) is an autosomal recessive neurodegenerative disorder affecting primarily neurons and cardiac cells, with symptoms including peripheral neuropathy, cardiomyopathy, diabetes, vision impairment, and hearing loss

• Because heterogeneity between patients is high, generation of representative and defined disease models to study FRDA pathology is in great demand

• FRDA is caused by expansion of a GAA trinucleotide sequence within the first intron of the Frataxin gene (FXN), which leads to its transcriptional repression

• Reduction of FXN protein levels impairs iron metabolism, iron-sulfur cluster formation and heme synthesis

• FRDA iPSCs can serve as a model to study GAA expansion mechanisms

• Development of somatic cell reprogramming technology and robust iPSC differentiation methods make it possible to generate neuronal and cardiac cells, which represent tissues affected by FRDA

• Improved genome editing approaches are allowing development of paired FRDA and GAA-excised isogenic cell lines

This box summarizes key points contained in the article.

Declaration of interest

M Napierala is in part supported by CRISPR Therapeutics. The sponsor had no role or any influence on the content of this manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was supported by grants from the National Institute of Neurological Disorders and Stroke, National Institutes of Health (R01 NS081366 and R21 NS101145 to M Napierala and R03 NS099953 to J S Napierala), the Friedreich’s Ataxia Research Alliance, Friedreich’s Ataxia Research Alliance Ireland, Muscular Dystrophy Association (MDA418838) and by a sponsored research agreement with CRISPR Therapeutics. M Napierala is a UAB Pittman Scholar.