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<p>Leber hereditary optic neuropathy (LHON), a maternally inherited mitochondrial disorder, results from point mutations in mitochondrial DNA (mtDNA), primarily affecting the <i>MT-ND4</i> 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 <i>MT-ND4</i> 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 <i>ND4</i> 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.</p>

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In vivo mitochondrial base editing restores genotype and visual function in a mouse model of LHON

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月23日

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  • Sanghun Kim,
  • Jieun Kim,
  • Seongkwang Cha,
  • Sungjin Ju,
  • Chae Jin Lim,
  • Seongho Hong,
  • Jiyoung Bae,
  • Yeji Oh,
  • Sungmo Jung,
  • Sol Pin Kim,
  • Hae-Sol Shin,
  • Jae Hee Yoon,
  • Jeeyoon Park,
  • Seungmin Ryou,
  • Soo-Yeon Lim,
  • Su Bin Lee,
  • Seung Hee Choi,
  • Soo-ji Park,
  • Chang Geun Choi,
  • Mihyun Choi,
  • Lark Kyun Kim,
  • Jiyoon Park,
  • Seonghyun Lee,
  • Kyoung Yul Seo,
  • Je Kyung Seong,
  • Kyoungmi Kim,
  • Jin-Soo Kim,
  • Hyunji Lee

摘要

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.