Using miRNA to identify new therapeutic pathways for dilated cardiomyopathy

SUMMARY
Dilated cardiomyopathy (DCM) associated heart failure is a leading cause of death and new therapeutic
strategies are needed. Pathogenic variants in over 50 genes contribute to DCM, but the molecular mechanisms
of disease are poorly understood. Much remains to be done to understand disease mechanisms and translate
the basic science into therapeutic strategies. The goal of this project is to identify targeted therapeutic strategies
for DCM. This goal aligns with my long-term career goal to become an independent researcher leading an
academic lab that focuses on better understanding human tissue-specific post-transcriptional regulation of gene
expression and developing mechanism-based therapeutics.
My primary hypothesis, supported by my preliminary results, is that some of the microRNA (miRNA)
upregulated in end stage heart failure (HF) exert a compensatory effect on the disease phenotype and that some
of these miRNAs have mutation-specific beneficial effects while others have effects independent of etiology. I
propose to study the mechanisms of both kinds of miRNA to identify new therapeutic targets.
In my earlier work, I developed an experimental platform to quantify several of the physiological phenotypes
of DCM in induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs). I used this system to identify a
potential therapeutic strategy (published and patented) for a specific variant of DCM. I used this system in my
preliminary work for this project to identify several miRNAs that ameliorate contractile phenotypes in iPSC-CMs
carrying DCM causal variants selected for their diverse molecular etiologies (PLN, RBM20, and TNNT2). As
hypothesized, some miRNAs had etiology-specific beneficial effects while others demonstrated improvement
across all etiologies.
My first aim is to test candidate miRNA targets to identify the mechanisms through which they exert the
beneficial effect in iPSC-CMs. My second aim is to identify the target genes of candidate miRNAs that regulate
sarcomeric and contractile functions and to test their effect in an alternative in vitro model (Engineered Heart
Tissues) and in a mouse model of DCM. My third aim is to test the hypothesis that the target space differs for
the miRNAs that have a mutation-specific effect and those that have a therapeutic effect on all DCM lines by
comparing the targets of mutation-specific and non-specific therapeutic miRNAs.
This project will expand our understanding of heart failure mechanisms and identify new points of
intervention for drug development. This project will also identify the etiology-specific and etiology-independent
disease mechanisms leading to DCM and test whether these differences can be exploited therapeutically. The
knowledge and tools generated will be of value to the DCM community and serve as a foundation for my
subsequent, independent work in developing personalized, mechanism-based therapeutic strategies.

Grant Number: 5R00HL165099-03
NIH Institute/Center: NIH
Principal Investigator: Francesca Briganti