Promising advancement in mitochondrial disease treatment: Korea University College of Medicine’s Prof. Hyunji Lee and team create a pioneering animal model

A research team led by Professor Hyunji Lee at Korea University College of Medicine’s Department of Medicine and including key contributors like co-first author researcher Seongho Hong and Edgene Inc. Team’s CTO Jin-Soo Kim, have achieved a groundbreaking success. They have managed to create mice with a unique alteration in their mitochondrial DNA which converts adenine (A) to guanine (G), a first-ever feat globally.

Mitochondria are often called the cell’s powerhouses, harboring self-contained DNA which is crucial for encoding energy metabolism-realated proteins. Flaws in this DNA can disrupt mitochondrial function, triggering a range of disorders in the brain, nerves, and muscles. Moreover, these mitochondrial defects are usually inherited maternally, meaning a mother’s mitochondrial issues can be passed down to her offspring, leading to mitochondrial diseases.

The popular CRISPR-Cas9 gene-editing tool is often used for DNA repair, but it falls short in mitochondrial DNA editing, as gRNA cannot be transported into the mitochondria.

Currently, there are two types of targeted base editing of mitochondrial DNA; DddA-derived cytosine base editors (DdCBEs), which induce C-to-T conversions, and transcription activator-like effector-linked deaminase (TALEDs), which catalyze A-to-G editing. Although DdCBE has been used in mice for mitochondrial C-to-T gene editing, successful use of TALED for A-to-G gene editing in animal studies has not been reported until now.

The team discovered that the original TALED version caused unwanted random DNA and RNA alterations within cells, causing developmental arrest of mouse embryos. To address this, they engineered TALED into a new variant, V28R-TALED, enhancing the precision of the DNA-modifying protein and significantly reducing unwanted DNA and RNA mutations.

Their breakthrough came when they used this improved TALED to microinject mouse zygotes, creating a disease model that showed mutations and symptoms characteristic of Leigh syndrome, a mitochondrial disease.

Sung-Ik Cho, the co-lead author of the study, shared his perspective, saying, “Mitochondrial genetic diseases can lead to severe symptoms. This research is a shining example of Korean researchers developing and advancing new technologies to tackle these issues. Our commitment is to continually push the boundaries of technology and conduct thorough research on side effects, aiming to offer new hope and viable solutions for those affected by mitochondrial genetic diseases.”

Researcher Seongho Hong, another co-lead author, conveyed his sentiments: “It’s an immense privilege to have played a role in this significant research effort aimed at treating mitochondrial diseases. The thought that our work could potentially offer hope to others adds an extra layer of fulfillment to our achievement.”

Prof. Hyunji Lee, the principal investigator of the study, remarked, “This research marks a critical step in the journey towards therapeutic applications. We’ve successfully implemented an enhanced mitochondrial gene editing technique in animals, which overcomes the random DNA and RNA alterations caused by previous methods. This progress brings us closer to developing effective treatments for mitochondrial diseases, which have long lacked sufficient treatment options.

This groundbreaking study, entitled ‘Engineering TALE-linked deaminases to facilitate precision adenine base editing in mitochondrial DNA,’ was published in the renowned international journal Cell (Impact Factor: 66.85) on January 4, 2024. Sung-Ik Cho (Yonsei University College of Medicine), Kayeong Lim (Brain Science Institute, Korea Institute of Science and Technology), and Seongho Hong (Korea University College of Medicine) collaborated as co-first authors. The co-corresponding authors include Professors Seonghyun Lee (Department of MetaBioHealth and School of Medicine, Sungkyunkwan University), Hyunji Lee (Korea University College of Medicine), and Jin-Soo Kim (National University of Singapore, CTO at Edgene, Inc.)