Non-cell-Autonomous Cardiomyocyte Regulation Complicates Gene Supplementation Therapy for Lmna-Associated Cardiac Defects in Mice
Brief intro:
- Author: Yueshen Sun, Congting Guo, Zhan Chen, Junsen Lin, Luzi Yang, Yueyang Zhang, Chenyang Wu, Dongyu Zhao, Blake Jardin, William T. Pu, Mingming Zhao, Erdan Dong, Xiaomin Hu, Shuyang Zhang, Yuxuan Guo
- Journal: JACC-Basic to Translational Science
- Doi: https://www.doi.org/10.1016/j.jacbts.2024.06.004
- Publication Date: 2024 Aug 21
Products/Services used in the paper
Quotation shows PackGene:AAV production was performed in house or at PackGene Biotech. We produced AAV9 as previously described.
Research Field:Lmna-Associated Cardiac Defects
AAV Serotype:AAV9
Targeted organ:liver, heart, skeletal muscles
Animal or cell line strain:mice
Abstract
The truncating mutations of LMNA are the major causes of cardiomyopathy. Here we studied 3 mouse models that carry germline, cardiomyocyte-specific, or genetic mosaic Lmna truncating mutations. Whereas the germline mutant manifested cardiac maturation defects, cardiomyocyte-specific mutation triggered pathological hypertrophy. In genetic mosaic analysis, no morphological defects were observed. Three adeno-associated virus (AAV) vectors were applied to addback lamin-A in a ubiquitous, cardiomyocyte-specific, or cardiomyocyte-excluded manner. Strikingly, only ubiquitous and cardiomyocyte-excluded AAV vectors mitigated the cardiac defects. Therefore, Lmna regulates cardiac morphology and function via a non-cell-autonomous mechanism. Noncardiomyocytes are key targets in AAV lamin-A therapy for Lmna-associated cardiac defects.
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