Research Stories

Engineered mitochondrial adenine base editor with reduced off-target effects on RNA with an animal model for genetic dis

Developing an improved mitochondrial adenine base editor, expanding the potential for creating a mouse model for mitochondrial disease research and treatment.

School of Medicine/Department of Metabiohealth

  • Engineered mitochondrial adenine base editor with reduced off-target effects on RNA with an animal model for genetic dis
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Professor Seonghyun Lee (Department of Precision Medicine, School of Medicine/Department of Metabiohealth) successfully developed engineered mitochondrial base editor and created mice with adenine base modifications at specific sequences of mitochondrial DNA, marking the world's first achievement. This research was conducted through a collaborative effort involving Yonsei University College of Medicine, KIST Brain Science Institute, Korea University College of Medicine, and Edgene Incorporation.

The mitochondria, existing as the energy source within cells, possess mitochondrial DNA that carries the genetic information for proteins essential in energy metabolism within its structure. Defects in this DNA lead to mitochondrial dysfunction, manifesting as various disorders in the brain, nerves, and muscles. Additionally, due to the unique maternal inheritance of mitochondria, maternal mitochondrial defects can be passed down to offspring, resulting in mitochondrial diseases in the descendants.

Current CRISPR-Cas9 gene editing technology is widely used for DNA correction, but it has limitations in mitochondrial DNA correction due to the inability of the guide RNA, which is used to recognize specific DNA sequences, to be transported into the mitochondria. As of now, the developed mitochondrial DNA correction technologies include DdCBE (Nature, 2020), capable of correcting C to T among the four DNA base sequences, and TALED (Cell, 2022), capable of correcting A to G. While there are reported cases of creating mice with mitochondrial C-to-T gene correction using DdCBE, there have been no reported instances of successful A-to-G gene correction in mitochondrial DNA in animal experiments.

The research team confirmed that the previously developed mitochondrial DNA editing technology, TALED, induces unintended random RNA mutations within cells. They discovered that when TALED is injected into mouse oocytes, normal embryo development does not occur. Therefore, they improved the TALED by engineering protein for precise DNA modification, resulting in the development of V28R-TALED. Through this improvement, the team observed a significant reduction in the unintended RNA mutations within cells, which were side effects of TALED. Furthermore, by microinjecting the improved TALED into mouse oocytes, the researchers successfully created mice carrying mutations associated with Leigh syndrome, a mitochondrial disorder, and exhibiting symptomatic features of the disease.

This study was published in the prestigious international journal, Cell (IF=66.85), on January 4, 2024 (Korean Standard Time).

Title: Engineering TALE-linked deaminases to facilitate precision adenine base editing in mitochondrial DNA


Author: Prof. Seonghyun Lee (Corresponding Author, Assistant Professor in Department of Precision Medicine, School of Medicine & Department of Metabiohealth)

Figure Schematic Drawing of Engineered TALED and its application