The evolving landscape of mitochondrial base editing: advances in precision, modeling, and therapeutic potential.

Abstract

The recent development of mitochondrial base editors (mitoBEs) has ushered in a transformational time that has overcome some long-standing limitations in the field of mitochondrial genetics. By closely tracing mitoBE development from the earliest tool mitochondria targeted TALENs to the most recent base editing systems that can precisely convert C•G → T•A and A•T → G•C, we review mitoBEs. We describe the development of recent advancements in mitoBEs including the generation of second generation mitoBEs (mitoBEs v2), which have evidence to identify over 70 mouse mtDNA mutations comparable to human pathogenic variants. Notably, in order to incorporate circular RNA (circRNA) as a delivery vector the editing efficiency has been increased by over 82 %, without experimental evidence of off-target effects. Taking advantage of these gains in technology, these mouse models of mitochondrial diseases, including those associated with Leigh syndrome and LHN, are highly faithful. These models have also confirmed that these specific mtDNA variants have pathological phenotypic evaluations, and have compared to previous editing strategies, mitoBEs v2 have demonstrated improved specificity, stability and safety. We finally discuss the future of mitochondrial base editing and outline the ways it will move forward towards therapeutic potentials in the treatment of the mitochondrial disorders and also in precision medicine.