The drug-elicitable alternative splicing module for tunable vector expression in the heart

  • Nat Cardiovasc Res. 2025 Jul;4(7):938-955. doi: 10.1038/s44161-025-00665-7.
Zhan Chen  #  1  2 ,  Luzi Yang  #  1  2 ,  Yueyang Zhang  1  2 ,  Jiting Li  1  2 ,  Yuhan Yang  1  2  3 ,  Yue Li  4 ,  Linwei Fan  2  5 ,  Wei Chen  6 ,  Lei Miao  6 ,  Jin Liu  1  2 ,  Gonglie Chen  1  2 ,  Ze Wang  1  2 ,  Yifei Li  7 ,  Fei Gao  8 ,  Jing Zhou  2  5  9  10 ,  Lemin Zheng  1  2  10 ,  Yan Zhang  1  2  9 ,  Dongyu Zhao  2  3 ,  William T Pu  11 ,  Ke Yang  4  12 ,  Erdan Dong  13  14  15  16  17 ,  Yuxuan Guo  18  19  20
Affiliations
  • 1. Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 2. State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
  • 3. Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 4. Vituner Therapeutics, Nantong, China.
  • 5. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 6. State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Molecular Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China.
  • 7. Ministry of Education Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.
  • 8. Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
  • 9. Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China.
  • 10. Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China.
  • 11. Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.
  • 12. Zhuhai Hengqin SBCVC Xinchuang Equity Investment Management Enterprise (Limited Partnership), Zhuhai, China.
  • 13. Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. [email protected].
  • 14. State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China. [email protected].
  • 15. Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China. [email protected].
  • 16. Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China. [email protected].
  • 17. Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China. [email protected].
  • 18. Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. [email protected].
  • 19. State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China. [email protected].
  • 20. Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 40514436 DOI: 10.1038/s44161-025-00665-7
Abstract

Adeno-associated viruses (AAVs) are commonly used for gene therapy, but a clinically relevant method to fine-tune AAV expression is lacking, restricting their therapeutic efficacy and safety. Here we develop the drug-elicitable alternative splicing module (DreAM), which is responsive to risdiplam, a Food and Drug Administration-approved alternative splicing modulator. Risdiplam activated DreAM-regulated AAV expression in a dose-dependent manner with a 2,000-fold inducible change, depending on the dose of risdiplam and the organ of interest. With a temporal resolution of 2 days, DreAM could transiently, reversibly and repeatedly activate AAV expression according to the frequency and duration of risdiplam administration. In this proof-of-concept study, we incorporated DreAM into the cardiomyocyte-specific, liver-detargeted AAV9-Tnnt2-miR122TS vector to transiently activate the cardiomyocyte regeneration factor YAP5SA. A dedifferentiation-proliferation-redifferentiation cycle was established in adult cardiomyocytes, improving cardiac regeneration after myocardial infarction while limiting animal death, AAV9-Tnnt2 expression in the liver and hepatic tumorigenesis. Therefore, DreAM may enhance the efficacy, safety and scope of gene therapy.

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