Systematic in vivo candidate evaluation uncovers therapeutic targets for LMNA dilated cardiomyopathy and risk of Lamin A toxicity

Background Dilated cardiomyopathy (DCM) is a severe, non-ischemic heart disease which ultimately results in heart failure (HF). Decades of research on DCM have revealed diverse aetiologies. Among them, familial DCM is the major form of DCM, with pathogenic variants in LMNA being the second most comm...

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Published in:	Journal of translational medicine Vol. 21; no. 1; pp. 1 - 690
Main Authors:	Tan, Chia Yee, Chan, Pui Shi, Tan, Hansen, Tan, Sung Wei, Lee, Chang Jie Mick, Wang, Jiong-Wei, Ye, Shu, Werner, Hendrikje, Loh, Ying Jie, Lee, Yin Loon, Ackers-Johnson, Matthew, Foo, Roger S. Y, Jiang, Jianming
Format:	Journal Article
Language:	English
Published:	London BioMed Central Ltd 16-10-2023 BioMed Central BMC
Subjects:	AAV Amino acids Analysis Candidates Cardiomyopathy Cardiomyopathy, Dilated Cardiotoxicity Care and treatment Congestive heart failure Connective tissue growth factor Diagnosis Dilated cardiomyopathy DNA damage DNA fingerprinting Ethylenediaminetetraacetic acid Fibrosis Gene expression Gene therapy Genetic aspects Health aspects Heart Heart diseases Inflammation Ischemia Laboratory animals Lamin A/C MAP kinase Plasmids Signal transduction Smad protein Smad3 protein Sun1 Therapeutic applications Therapeutic targets TOR protein Toxicity Transcriptomes Transforming growth factors Viruses Singapore
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Summary:	Background Dilated cardiomyopathy (DCM) is a severe, non-ischemic heart disease which ultimately results in heart failure (HF). Decades of research on DCM have revealed diverse aetiologies. Among them, familial DCM is the major form of DCM, with pathogenic variants in LMNA being the second most common form of autosomal dominant DCM. LMNA DCM is a multifactorial and complex disease with no specific treatment thus far. Many studies have demonstrated that perturbing candidates related to various dysregulated pathways ameliorate LMNA DCM. However, it is unknown whether these candidates could serve as potential therapeutic targets especially in long term efficacy. Methods We evaluated 14 potential candidates including Lmna gene products (Lamin A and Lamin C), key signaling pathways (Tgf[beta]/Smad, mTor and Fgf/Mapk), calcium handling, proliferation regulators and modifiers of LINC complex function in a cardiac specific Lmna DCM model. Positive candidates for improved cardiac function were further assessed by survival analysis. Suppressive roles and mechanisms of these candidates in ameliorating Lmna DCM were dissected by comparing marker gene expression, Tgf[beta] signaling pathway activation, fibrosis, inflammation, proliferation and DNA damage. Furthermore, transcriptome profiling compared the differences between Lamin A and Lamin C treatment. Results Cardiac function was restored by several positive candidates (Smad3, Yy1, Bmp7, Ctgf, aYAP1, Sun1, Lamin A, and Lamin C), which significantly correlated with suppression of HF/fibrosis marker expression and cardiac fibrosis in Lmna DCM. Lamin C or Sun1 shRNA administration achieved consistent, prolonged survival which highly correlated with reduced heart inflammation and DNA damage. Importantly, Lamin A treatment improved but could not reproduce long term survival, and Lamin A administration to healthy hearts itself induced DCM. Mechanistically, we identified this lapse as caused by a dose-dependent toxicity of Lamin A, which was independent from its maturation. Conclusions In vivo candidate evaluation revealed that supplementation of Lamin C or knockdown of Sun1 significantly suppressed Lmna DCM and achieve prolonged survival. Conversely, Lamin A supplementation did not rescue long term survival and may impart detrimental cardiotoxicity risk. This study highlights a potential of advancing Lamin C and Sun1 as therapeutic targets for the treatment of LMNA DCM. Graphical Keywords: Dilated cardiomyopathy, Lamin A/C, Sun1, Gene therapy, AAV, Fibrosis, Inflammation
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1479-5876 1479-5876
DOI:	10.1186/s12967-023-04542-4