2. Academic Validation
  3. PLN-L31A/I40A for the treatment of inherited heart disease caused by PLN-R14del mutations

PLN-L31A/I40A for the treatment of inherited heart disease caused by PLN-R14del mutations

  • Acta Pharmacol Sin. 2026 Jan 16. doi: 10.1038/s41401-025-01711-7.
Zi-Yang Chen # 1 2,  Ren Guo # 1,  Min Wang 1,  Si-Jia Ji 1 2 3,  Jing-Wei Zhang 1 2 3,  Hui-Xiang Zheng 1 2 3,  Shi-Tong Wang 1 2,  Xin Xie 4 5 6 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2 School of Pharmacy, University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China.
  • 4 State Key Laboratory of Drug Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 5 School of Pharmacy, University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 6 School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China. [email protected].
  • 7 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264119, China. [email protected].
  • # Contributed equally.
PMID: 41545752 DOI: 10.1038/s41401-025-01711-7
Abstract

Phospholamban (PLN) is a regulatory protein of the SERCA2α calcium transporter, which plays an important role in maintaining calcium homeostasis in cardiomyocytes. Deletion of the 14th arginine of PLN (PLN-R14del) leads to dysregulation of SERCA2α and PLN aggregation, and is a common cause of dilated cardiomyopathy. In this study, by using CRISPR-Cas9 gene editing technology, we constructed the PLN-R14del mouse model and hESCs. The PLNR14del/R14del mice developed severe ventricular dilation, cardiac fibrosis, and PLN aggregation, as well as premature death due to heart failure. Reduced cardiomyocyte functions and PLN aggregation were also observed in the human PLNR14del/WT cardiomyocytes differentiated from gene-edited hESCs. AAV delivery of PLN-L31A/I40A, which blocks PLN-R14del and SERCA2α interaction but without blocking the function of the latter, provided a therapeutic effect in both mice and human cardiomyocytes. These results not only suggest that PLN-L31A/I40A gene therapy is practical, but also suggest that blocking the interaction between PLN-R14del and SERCA2α with Other modalities, such as small molecules, might also be beneficial.

Keywords

CRISPR-Cas9; PLN-L31A/I40A; PLN-R14del; dilated cardiomyopathy; human embryonic stem cell; phospholamban.

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