Mechanistic Insights and Therapeutic Approaches for LEMD2-Associated Cardiomyopathy

• Applicant: Dr. Ruping Chen
• Subject Area: Cardiology, Angiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 568672677

Studying genetically determined primary cardiomyopathies is an auspicious approach to establishing fundamental disease mechanisms and novel therapeutic options leading to heart failure and sudden cardiac death. In our previous study, we identified a homozygous missense mutation in LEMD2 c.38T>G (p.L13R) through exome sequencing, a novel target gene associated with inherited cardiomyopathy. LEMD2 is an inner nuclear membrane protein and a binding partner of LMNA, which stands as the second most prevalent disease-associated gene accounting for about 6% of dilated cardiomyopathy (DCM) cases. The clinical presentation of LEMD2 p.L13R affected shares similar clinical features with LMNA-associated cardiomyopathy, characterized by DCM with ventricular arrhythmias and fibrosis. To investigate the underlying mechanisms, we generated a Lemd2 p.L13R knock-in (KI) mouse model, effectively recapitulating the patient phenotype. Mechanistically, the LEMD2 mutation disrupts nuclear membrane structure, resulting in increased nuclear envelope ruptures under increased stiffness with age. Cells with ruptured nuclear membranes lose their ability to adequately ensure DNA repair, leading to increased DNA damage. Ruptured nuclei activate the cGAS/STING/interferon pathway, collectively promoting premature cell senescence along with associated inflammation and fibrosis. Currently, only general heart failure therapy is available, lacking tailed approaches for severely affected patients. This proposal aims to develop potential clinical therapies based on our previous findings. The key objectives encompass three aspects. Firstly, we will assess the alterations in mechanotransduction, analyzing alterations in phosphorylation and localization of involved mechanosensor in our KI model. Additionally, we will evaluate the cardiac phenotype under mechanical stress in KI models to investigate the mechanical role in the pathogenesis of LEMD2-associated cardiomyopathy. Secondly, we will disrupt the LINC complex through AAV9-DNmSun1 virus delivery to evaluate the rescue effect on the cardiac phenotype both in young-aged KI mice under mechanical stress conditions and in KI mice with natural aging. Lastly, we will determine if blocking the cGAS/STING pathway with inhibitors can rescue the cardiac phenotype under stress conditions in our mouse model. Insights gained from AAV9-DNmSun1 virus delivery and small molecule drug assessment will facilitate our efforts in developing potential new therapeutic treatments for LEMD2 p.L13R patients.

• DFG Programme: Research Grants