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

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

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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