Olmesartan Restores LMNA Function in Haploinsufficient Cardiomyocytes

Area of Science:

• Cardiovascular Research
• Genetics and Genomics
• Drug Discovery and Development

Background:

• Gene mutations are a significant cause of heart failure, but specific mutations affect small patient populations.
• Repurposing existing FDA-approved drugs is an efficient strategy for developing targeted therapies for rare genetic mutations.

Purpose of the Study:

• To identify FDA-approved compounds capable of reversing the transcriptional effects of LMNA gene knockdown.
• To validate potential drug candidates using patient-specific induced pluripotent stem cell-derived cardiomyocytes.

Main Methods:

• In silico screening of the National Institutes of Health Library of Integrated Network-Based Cellular Signatures database.
• In vitro validation using patient-derived cardiomyocytes, including gene expression profiling, electrophysiology, and protein analysis.

Main Results:

• Several angiotensin receptor blockers were identified, with olmesartan showing significant efficacy.
• Olmesartan enhanced sarcomeric gene expression, improved contraction rate and force, and reduced arrhythmogenic potential.
• Olmesartan decreased extracellular signal-regulated kinase 1 phosphorylation in LMNA-mutant cardiomyocytes.

Conclusions:

• In silico screening combined with in vitro validation using induced pluripotent stem cell models is effective for identifying repositionable therapies.
• This approach shows promise for treating monogenic cardiomyopathies, such as those caused by LMNA mutations.