Key result
Olmesartan reverses LMNA mutation transcriptional signatures and increases contraction velocity in patient-derived iPSC-cardiomyocytes.
Why the study?
High drug development costs preclude developing targeted therapies for rare diseases such as monogenic cardiomyopathies.
Transcriptomic profiling using large-scale datasets like LINCS offers a viable computational approach to repurpose FDA-approved drugs for rare monogenic cardiomyopathies.
Hypothesis-generating for olmesartan in LMNA cardiomyopathy; leaves open clinical translation pending prospective trials.
The cost of drug development from initial concept to FDA approval has been estimated to be about 2.6 billion USD. 1 This cost precludes development of targeted therapies for rare diseases such as monogenetic cardiomyopathies. As part of the Library of Integrated Network-based Cellular Signatures (LINCS) program funded by the NIH, the Broad Institute of MIT has publicly released transcriptional profiles quantifying the effects of more than 25,000 perturbagens on the expression of 978 genes in up to 77 cell lines. 2 Transcriptomics has been shown to be a powerful tool in repurposing drugs 3,4 and this dataset affords us the unique opportunity to systematically identify small molecule mimics or inhibitors of specific genes, thereby identifying novel treatments for genetic disorders. In this report, we take this approach to identify a novel drug therapy for a monogenic form of familial dilated cardiomyopathy with the transcriptional profile of FDA approved drugs. This approach could potentially be replicated for a wide range of monogenic diseases.
No takes yet. Share an insight, caveat, or question.
Kort et al. (2019) studied Familial dilated cardiomyopathy (LMNA mutation). Olmesartan vs. DMSO control was evaluated on Reversal of LMNA knockdown transcriptional signature and improvement in cardiomyocyte contractility. Olmesartan reversed the transcriptional signature of LMNA mutation and markedly increased contraction velocity and beating rate in patient-derived iPSC-cardiomyocytes compared to vehicle control.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: