In vivo mitochondrial base editing restores genotype and visual function in a mouse model of LHON
Leber hereditary optic neuropathy (LHON), a maternally inherited mitochondrial disorder, results from point mutations in mitochondrial DNA (mtDNA), primarily affecting the MT-ND4 gene. To date, no animal model harboring authentic LHON mutations has been available, limiting therapeutic development. However, when we attempted to generate such models using mitochondrial base editors, we found that activity-enhanced DddA11-based cytosine base editors (DdCBEs) induce off-target mtDNA mutations and developmental arrest in embryos. Using a high-fidelity DdCBE (Hifi-DdCBE), we successfully generate mice carrying the pathogenic MT-ND4 G11778A mutation, the most common LHON variant. These mice exhibit hallmark phenotypes, including retinal ganglion cell loss and impaired visual function. Intravitreal delivery of adeno-associated virus encoding TALE-linked deaminases (TALEDs) restores both phenotype and genotype in these mice. Furthermore, optimized TALEDs corrects the ND4 mutation with minimal off-target effects in LHON patient-derived cells, highlighting the potential of mitochondrial base editing as a therapeutic strategy for mtDNA-associated diseases.
Authors
- Jae Hee Yoon (ORCID: https://orcid.org/0000-0001-9159-8375)
- Jeeyoon Park (ORCID: https://orcid.org/0000-0002-1554-5551)
- Jiyoung Bae (ORCID: https://orcid.org/0000-0001-7872-7689)
- Soo-Ji Park (ORCID: https://orcid.org/0009-0003-0417-7487)
- Sol Pin Kim (ORCID: https://orcid.org/0000-0003-1625-5756)
- Chang Geun Choi
- Je Kyung Seong (ORCID: https://orcid.org/0000-0003-1177-6958)
- Mihyun Choi (ORCID: https://orcid.org/0000-0003-2420-0907)
- Hae-Sol Shin
- Seongkwang Cha (ORCID: https://orcid.org/0000-0002-0859-2368)
- Kyoung Yul Seo (ORCID: https://orcid.org/0000-0002-9855-1980)
- Lark Kyun Kim (ORCID: https://orcid.org/0000-0001-5983-4470)
- Seungmin Ryou
- Kyoungmi Kim (ORCID: https://orcid.org/0000-0003-0941-806X)
- Hyunji Lee (ORCID: https://orcid.org/0000-0001-9957-9275)
- Jin‐Soo Kim (ORCID: https://orcid.org/0000-0003-4847-1306)
- Ji Eun Kim (ORCID: https://orcid.org/0000-0003-3094-2229)
- Jong Cheol Park (ORCID: https://orcid.org/0000-0002-8859-5111)
- Sanghun Kim (ORCID: https://orcid.org/0000-0003-2745-1728)
- Seongho Hong (ORCID: https://orcid.org/0000-0002-8787-6974)
- Sungmo Jung
- Chae Jin Lim (ORCID: https://orcid.org/0000-0002-2920-6876)
- Seonghyun Lee (ORCID: https://orcid.org/0000-0003-1972-7106)
- Shaoqing Ju
- Seung Hee Choi
- Sooyeon Lim (ORCID: https://orcid.org/0000-0002-5589-1299)
- Yeji Oh
- Su Bin Lee
Institutions
- Seoul National University (KR)
- National University of Singapore (SG)
- Yonsei University (KR)
- Korea University (KR)
- Severance Hospital (KR)
- Korea University Medical Center (KR)
- National University College (PR)
- Macrogen (South Korea) (KR)
- Gangnam Severance Hospital (KR)
- Yonsei University Health System (KR)
- Korea University (JP)
- Sungkyunkwan University (KR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-23
- DOI
- https://doi.org/10.1038/s41467-025-66600-3
- Citations
- 1
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- National Research Foundation
- Korea Institute for Advancement of Technology
- National Research Foundation of Korea
- Ministry of SMEs and Startups
- Ministry of Science and ICT, South Korea