Using Gene Activity Analysis to Repurpose Existing Drugs
for Genetic Heart Disease
by Amanda Chase, PhD
April 2, 2025
Although deaths from heart disease have been declining due to advances in treatment, the number of people living with heart failure and related health problems is increasing. Some cases of heart failure are caused by genetic mutations, which can disrupt the normal function of heart cells. Collectively, there is a substantial burden of heart failure from genetic mutations, although heart failure associated with any one mutation accounts for only a small portion. For this reason, developing new drugs tailored to these patients, while urgently needed, is especially expensive and slow.
In a recently published study in Circulation, researchers, led by co-first authors Eric Kort and Stanford Cardiovascular Institute member Nazish Sayed, explored an innovative approach to finding treatments for genetic heart disease using a combination of computer-based (in silico) analysis and testing with patient-derived heart cells (in vitro). In this study, researchers focused on mutations in the LMNA gene associated with familial dilated cardiomyopathy and used their approach to identify a previously approved drug that could reverse harmful effects of the LMNA mutation at the genetic level.
Data from the LINCS dataset was analyzed to identify gene-targeting drugs for heart failure due to mutations in LMNA. The candidate drugs were validated by testing in patient and healthy control iPSC-derived heart cells.
Transcriptomics is the study of how genes are turned on or off inside cells. The technique is important for understanding how a disease can change gene activity and to identify drugs that can correct those changes. Importantly, transcriptomics allows researchers to look at thousands of genes at one time, which makes it a powerful tool for drug repurposing. Researchers can scan a large database of gene activity to match diseases with FDA-approved drugs that could restore normal function. In this manuscript, the team used a large public databased called the Library of Integrated Network-based Cellular Signatures (LINCS). Their analysis identified Olmesartan as a promising candidate for patients with heart failure due to a mutation in the LMNA gene.
They then tested Olmesartan in heart cells derived from patients with LMNA mutations and found that the drug was able to improve heart cell function, reduced abnormal rhythms, and restored gene function that had been disrupted by the mutation. Together, this analysis suggests a novel application of Olmesartan for patients with heart failure related to LMNA mutations.
This study also highlights a promising strategy for repurposing existing drugs to treat rare genetic diseases, offering a faster and more cost-effective alternative to traditional drug development.
Other Stanford Cardiovascular Institute (SCVI) members part of the research team include Chun Liu, Gema Mondéjar-Parreño, Sean Wu, and Joseph Wu. Senior author is CVI-associated member Stefan Jovinge, who is also affiliated with Spectrum Health & Van Andel Institute in Michigan and Lund University in Sweden. The team also includes Jens Forsberg and Emily Eugster at Spectrum Health & Van Andel Institute in Michigan.
Dr. Nazish Sayed