PLN-L31A/I40A for the treatment of inherited heart disease caused by PLN-R14del mutations
文献类型：期刊论文
| 作者 | Chen, Zi-yang3,4; Guo, Ren4; Wang, Min4; Ji, Si-jia2,3,4; Zhang, Jing-wei2,3,4; Zheng, Hui-xiang2,3,4; Wang, Shi-tong3,4; Xie, Xin1,2,3,4 |
| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2026-01-16 |
| 页码 | 13 |
| 关键词 | dilated cardiomyopathy phospholamban PLN-R14del PLN-L31A/I40A CRISPR-Cas9 human embryonic stem cell |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/s41401-025-01711-7 |
| 英文摘要 | Phospholamban (PLN) is a regulatory protein of the SERCA2 alpha 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 SERCA2 alpha 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 SERCA2 alpha 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 SERCA2 alpha with other modalities, such as small molecules, might also be beneficial. |
| WOS关键词 | DILATED CARDIOMYOPATHY ; PHOSPHOLAMBAN ; GENE ; PREVALENCE ; FAMILY ; RISK |
| 资助项目 | Ministry of Science and Technology of China[2022YFA1104700] ; Ministry of Science and Technology of China[2022ZD0204700] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[82330113] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[2022280] ; Fundamental Research Projects of Science & Technology Innovation and Development Plan in Yantai City[2023JCYJ063] ; Taishan Scholars Program |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001662290900001 |
| 出版者 | NATURE PUBL GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/322625]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Xie, Xin |
| 作者单位 | 1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264119, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China 3.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Zi-yang,Guo, Ren,Wang, Min,et al. PLN-L31A/I40A for the treatment of inherited heart disease caused by PLN-R14del mutations[J]. ACTA PHARMACOLOGICA SINICA,2026:13. |
| APA | Chen, Zi-yang.,Guo, Ren.,Wang, Min.,Ji, Si-jia.,Zhang, Jing-wei.,...&Xie, Xin.(2026).PLN-L31A/I40A for the treatment of inherited heart disease caused by PLN-R14del mutations.ACTA PHARMACOLOGICA SINICA,13. |
| MLA | Chen, Zi-yang,et al."PLN-L31A/I40A for the treatment of inherited heart disease caused by PLN-R14del mutations".ACTA PHARMACOLOGICA SINICA (2026):13. |
入库方式： OAI收割
来源：上海药物研究所
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