2. Academic Validation
  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. donged@bjmu.edu.cn.
  • 14 State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China. donged@bjmu.edu.cn.
  • 15 Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China. donged@bjmu.edu.cn.
  • 16 Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China. donged@bjmu.edu.cn.
  • 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. donged@bjmu.edu.cn.
  • 18 Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. guo@bjmu.edu.cn.
  • 19 State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China. guo@bjmu.edu.cn.
  • 20 Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China. guo@bjmu.edu.cn.
  • # 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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