Journal of Pharmaceutical Care & Health Systems
Open Access

Antisense inhibition of HERNA1 reverses cardiac pathology and progression to heart failure

6^th Asia-Pacific Pharma Congress

July 11-13, 2016 Kuala Lumpur, Malaysia

Jaya Krishnan

Goethe-University Frankfurt, Germany
Targeted Transgenesis Ltd., UK

Posters & Accepted Abstracts: J Pharma Care Health Sys

Abstract :

Recent efforts have identified a subclass of non-coding RNAs templated at genomic enhancers (eRNAs) with gene regulatory function. Due to their genomic position we postulated their function in modulating signal-dependent tissue-specific transcriptional responses. Here we identify HERNA1, a conserved hypoxia-inducible factor (HIF) activated, cardiac-specific eRNA that integrates myocardial hypoxia signaling to regulate expression of a nearby pro-hypertrophic gene cluster in humans and mice. Elevated HERNA1 expression correlates with hypertrophic cardiomyopathy, but inversely correlates with dilated cardiomyopathy in humans. Through gain- and loss-of-function studies, we observe a requirement for HERNA1 in the development of stress-dependent hypertrophic cardiomyopathy and mechanistically, identify direct HERNA1 interaction at the promoters of its downstream targets. In vivo delivery of antisense oligonucleotides targeting HERNA1 reverses cardiac pathogenesis, inhibits heart failure progression and increases overall survival in animals. Taken together, these data unveil a novel heart-specific stress-dependent eRNA pathway and reveals a new strategy for tissue/cell type-specific therapeutics.

Biography :

Email: jaya.krishnan@csc.mrc.ac.uk