Modeling mitochondrial DNA diseases: from base editing to pluripotent stem‐cell‐derived organoids

Author:

Tolle Isabella1,Tiranti Valeria2ORCID,Prigione Alessandro1ORCID

Affiliation:

1. Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty Heinrich Heine University Düsseldorf Germany

2. Unit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy

Abstract

AbstractMitochondrial DNA (mtDNA) diseases are multi‐systemic disorders caused by mutations affecting a fraction or the entirety of mtDNA copies. Currently, there are no approved therapies for the majority of mtDNA diseases. Challenges associated with engineering mtDNA have in fact hindered the study of mtDNA defects. Despite these difficulties, it has been possible to develop valuable cellular and animal models of mtDNA diseases. Here, we describe recent advances in base editing of mtDNA and the generation of three‐dimensional organoids from patient‐derived human‐induced pluripotent stem cells (iPSCs). Together with already available modeling tools, the combination of these novel technologies could allow determining the impact of specific mtDNA mutations in distinct human cell types and might help uncover how mtDNA mutation load segregates during tissue organization. iPSC‐derived organoids could also represent a platform for the identification of treatment strategies and for probing the in vitro effectiveness of mtDNA gene therapies. These studies have the potential to increase our mechanistic understanding of mtDNA diseases and may open the way to highly needed and personalized therapeutic interventions.

Funder

Bundesministerium für Bildung und Forschung

United Mitochondrial Disease Foundation

Fondazione Pierfranco e Luisa Mariani

Publisher

Springer Science and Business Media LLC

Subject

Genetics,Molecular Biology,Biochemistry

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