2. Academic Validation
  3. Gene therapy prevents onset of mitochondrial cardiomyopathy in neonatal mice with Ndufs6 deficiency

Gene therapy prevents onset of mitochondrial cardiomyopathy in neonatal mice with Ndufs6 deficiency

  • Cell Death Discov. 2025 May 22;11(1):249. doi: 10.1038/s41420-025-02524-7.
Xiaoxian Zhang # 1 2,  Li Huang # 1 2 3,  Cheng Li # 2 4,  Jinjuan Yang 1,  Fuyu Duan 2,  Qiang Su 2,  Yuelin Zhang 5,  Meng Kou 1,  Xiaoya Zhou 1 2,  Liyan Guo 1,  Shaoxiang Chen 1,  Yongxia Niu 2,  Ziyue Li 1,  Sihua Ou 1,  Min Zhang 2,  Kenneth King-Yip Cheng 6,  Jianlong Wu 3,  Xiang Xu 7,  Qizhou Lian 8 9 10
Affiliations

Affiliations

  • 1 Prenatal Diagnostic Center and Cord Blood Bank, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China.
  • 2 Faculty of Synthetic Biology, Shenzhen University of Advanced Technology; CAS Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
  • 3 Department of Pharmacy, Shenzhen Clinical Research Center for Neurological Diseases, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China.
  • 4 Department of Pain Medicine, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, China.
  • 5 Department of Emergency Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
  • 6 Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China.
  • 7 State Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China.
  • 8 Prenatal Diagnostic Center and Cord Blood Bank, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China. qz.lian@siat.ac.cn.
  • 9 Faculty of Synthetic Biology, Shenzhen University of Advanced Technology; CAS Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. qz.lian@siat.ac.cn.
  • 10 Center for Translational Stem Cell Biology, Hong Kong, and State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, China. qz.lian@siat.ac.cn.
  • # Contributed equally.
PMID: 40399258 DOI: 10.1038/s41420-025-02524-7
Abstract

Mutations in genes affecting mitochondrial complex I (CI) can lead to mitochondrial cardiomyopathy (MCM) yet no effective treatment. This study sought to determine whether adeno-associated virus 9 (AAV9)-based gene therapy could prevent or rescue Ndufs6 deficiency-induced MCM at different disease stages. Using Ndufs6gt/gt mice to mimic MCM, cardiac dysfunction was evident at week 4 post-birth, showing reduced ejection fraction, CI activity, increased fibrosis, mitochondrial fission, and disrupted cristae. Neonatal and adult mice were intravenously given AAV9-hNdufs6 (1e14 vg kg-1). AAV9-hNdufs6 therapy effectively prevented neonatal mice's cardiac dysfunction onset, preserving CI activity and cristae structure for 11 months. In contrast, therapy in adult mice post-disease onset failed to reverse or halt progression of heart dilation and failure after 3 months, showing mitochondrial abnormalities and cardiomyocyte Apoptosis. Mechanistically, adult mouse Kupffer cells demonstrated enhanced phagocytic capabilities compared to neonatal mice, with higher expression levels of AAV9 cell surface receptors observed in neonatal mouse hearts, rendering neonatal mice more responsive to AAV9-mediated gene therapy for heart tissue. Additionally, AAV9-hNdufs6 gene therapy initiated at an early stage increased Ndufs6 expression in cardiac tissue, preserved mitochondrial structure and function, prevented cardiomyocyte fibrosis through modulation of the AMPK/Drp1 signaling pathway. In conclusion, early intervention with AAV9-hNdufs6 gene therapy can effectively prevent the onset of MCM, but intervention after disease onset has limited efficacy.

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