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

Acta Pharmacologica Sinica volume 47, pages 1191–1203 (2026) Cite this article

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.

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Fig. 1: Construction of PLN-R14del mice.
The alternative text for this image may have been generated using AI.
Fig. 2: Ventricular dilation and heart failure in PLN-R14del mice during development.
The alternative text for this image may have been generated using AI.
Fig. 3: Cardiac fibrosis and abnormal PLN aggregation in PLN-R14del mice.
The alternative text for this image may have been generated using AI.
Fig. 4: Fibrosis and heart failure related genes expression in PLN-R14del mice hearts.
The alternative text for this image may have been generated using AI.
Fig. 5: Expression of PLN L31A/I40A provides protection in PLNR14del/R14del mice.
The alternative text for this image may have been generated using AI.
Fig. 6: Construction of hESC line carrying PLNR14del/WT mutation.
The alternative text for this image may have been generated using AI.
Fig. 7: Expression of PLN L31A/I40A reduces PLN R14del-induced anomalies in cardiomyocytes derived from hESCs.
The alternative text for this image may have been generated using AI.

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Acknowledgements

This work was supported by grants from the Ministry of Science and Technology of China (2022YFA1104700 and 2022ZD0204700 to XX), the National Natural Science Foundation of China (82121005 and 82330113 to XX), Youth Innovation Promotion Association of the Chinese Academy of Sciences grants (2022280 to RG), Fundamental Research Projects of Science & Technology Innovation and Development Plan in Yantai City (2023JCYJ063 to RG), and Taishan Scholars Program to XX.

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  1. These authors contributed equally: Zi-yang Chen, Ren Guo

Authors and 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

    Zi-yang Chen, Ren Guo, Min Wang, Si-jia Ji, Jing-wei Zhang, Hui-xiang Zheng, Shi-tong Wang & Xin Xie

  2. School of Pharmacy, University of Chinese Academy of Sciences, Beijing, 100049, China

    Zi-yang Chen, Si-jia Ji, Jing-wei Zhang, Hui-xiang Zheng, Shi-tong Wang & Xin Xie

  3. School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China

    Si-jia Ji, Jing-wei Zhang, Hui-xiang Zheng & Xin Xie

  4. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264119, China

    Xin Xie

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  1. Zi-yang Chen
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Contributions

ZYC and RG designed and conducted most of the experiments, analyzed the results, and wrote the paper; MW constructed the PLN gene-edited mice; SJJ, JWZ, HXZ, and STW provided technical assistance in this study; XX conceived the idea and supervised the study, analyzed the results, and wrote the paper. All authors reviewed the results and approved the final version of the manuscript.

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Correspondence to Xin Xie.

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The corresponding author Xin Xie is a member of the Editorial Board of the journal Acta Pharmacologica Sinica, but she has not been involved in the peer-review or decision-making process for this manuscript.

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Chen, Zy., Guo, R., Wang, M. et al. PLN-L31A/I40A for the treatment of inherited heart disease caused by PLN-R14del mutations. Acta Pharmacol Sin 47, 1191–1203 (2026). https://doi.org/10.1038/s41401-025-01711-7

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