These models are part of the company’s MyHeart platform, an approach that aims to capture the major clinical symptoms of FA.
“We are very excited by the outcome of this study, and hope this will accelerate the development of safe and effective new therapies for FRDA patients. Also, by demonstrating the biomimetic capabilities of our MyHeart Platform for modeling diseased hearts, we are hoping to establish new standards for creating a proprietary library of disease models and expand our presence in drug discovery and precision medicine,” Kevin Costa, PhD, chief scientific officer of NovoHeart, said in a press release.
The research, “Modeling Cardiac Dysfunction of Friedreich’s Ataxia Using Ventricular Sheets, Tissues and Chambers Engineered From Human Pluripotent Stem Cells,” was recently presented at the International Society for Stem Cell Research (ISSCR) 2018 Annual Meeting, in Melbourne, Australia. The abstract is available on page 567 of the ISSCR meeting’s poster abstract book.
FA is caused by a mutation in the FXN gene, which contains instructions to make a protein called frataxin. This protein is critical for the proper functioning of mitochondria, which provide power to cells.
Given its high energy requirements, the heart is one of the first organs affected by the lack of frataxin, leading to cardiac abnormalities such as heart failure, myocardial fibrosis — scarring in the muscles of the heart — or hypertrophic cardiomyopathy, in which the heart muscle (myocardium) becomes abnormally thick.
Existing transgenic mouse models of FA are not able to reproduce the genetic profile, severity, and symptoms of human patients.
To address this limitation, the research team developed human ventricular cardiac anisotropic sheets (hvCAS) — an approach that mimics the heart’s structural and functional properties — and tissue strips (hvCTS), which are intended to evaluate the effects of potential medications and disease conditions in the heart’s ability to contract.
To generate hvCAS and hvCTS, the investigators used ventricular cardiomyocytes (VCMs), or cardiac muscle cells, derived from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), which have the ability to renew themselves and are able to develop into all cells of the adult body.
This strategy is intended to model the electrophysiological — which refers to the nerve-signal transmission — and contractile defects of the heart in FA patients.
Using a harmless virus containing short hairpin RNAs (shRNAs) — artificial RNA molecules intended to inhibit genes — the researchers observed significant suppression of frataxin levels in VCMs, including FA-specific VCMs, compared with controls.
Analysis of hvCAS revealed electrophysiological defects of hESCs and FA-specific iPSCs, matching what is observed in patient electrocardiograms. In the hvCTS approach, contractility was consistently suppressed in cells given shRNAs and in those mimicking FA. This result correlated with the amount of frataxin present.
The researchers then performed experiments to correct the FA-related deficits by inducing FXN expression in stem cells treated with shRNAs and in FA-specific tissue strips. This led to a reversal in the reduction of contractility in the two models.
Scientists are also currently testing cardiac organoid chambers to obtain other clinically relevant parameters, such as cardiac output, which is the amount of blood pumped by the heart. According to Novoheart, these organoid chambers are the only available human cardiac tissue model, on a larger scale, that mimics fluid pumping similar to natural heart.
According to the researchers, these human-based FA models provide “a platform suitable to facilitate the studies of disease pathogenesis and pharmaceutical testing.”