Heart-In-A-Jar Platform Humanizing Preclinical Research
By Deborah Borfitz
January 6, 2020 | Stem cell biotech company Novoheart has been bioengineering miniature human hearts as a platform for drug discovery and development for several top pharmaceutical firms, notably for human conditions without a good animal model for preclinical testing. Novoheart’s thumb-sized human “heart-in-a-jar” models can both contract and eject blood-like fluid, making it possible to measure how well the heart is pumping, according to Chief Executive Officer and Scientific Co-founder Ronald Li.
The pumping capability was one of the more compelling features of the three-dimensional (3-D) organ construct for AstraZeneca, which is looking to screen drug candidates for treating heart failure with preserved ejection fraction—a common condition especially among the elderly and in women—with no effective therapy available, says Li. Novoheart’s cardiac tissue engineering technology, known as the MyHeart Platform, also held appeal for Pfizer, which has used it to model both electrical and mechanical defects of the heart in patients with the neurodegenerative disease Friedreich’s ataxia (FRDA).
In a study published earlier this year in Stem Cell Research & Therapy, the FRDA models demonstrated utility in evaluating novel therapeutics and disease progression. Study results highlighted the potential of small molecules or gene therapy for suppressing or reversing the cardiac symptoms of FRDA.
Novoheart makes heart models from patient donors that carry the same disease mutations, allowing for efficacy screening, as well as heart models from normal healthy donors for toxicity screening, says Li, who is also director of Ming-Wai Lau Centre for Reparative Medicine, HK node, Karolinska Institutet, in Sweden. “It takes 10 to 12 years and several billion U.S. dollars to develop medicines and statistically we know that 95% of time they fail and… the top cause often has to do with side effects to the heart.”
Unlike animal models, Novoheart’s heart-in-a-jar—more formally termed a human ventricular cardiac organoid chamber (hvCOC)—gives drug developers an effective tool for preclinical testing of drug candidates. The process of building a miniature heart begins with a few drops of blood, which get turned into pluripotent stem cells that can subsequently become a range of different cardiac cells and tissues mimicking the physical and mechanical properties of those in the targeted population, Li explains.
In addition to the heart-in-a-jar model, Novoheart’s MyHeart product line includes stem cell-derived ventricular cardiac muscle cells, a microfabricated substrate for quantifying risk of cardiac electrical disturbances and a cardiac tissue strip for assessing cardiac contractility under different drug and disease conditions.
The human heart-in-a-jar platform is conceptually similar but structurally different from engineered heart-on-a-chip systems that some call 3-D but are in fact flat, two-dimensional, tissue models, says Li. Heart chips can measure contractile force but not the pressure the heart exerts while beating. A clinically relevant pressure reading requires a pouch to generate the inflow and outflow of blood-mimicking fluid to the manufactured heart chamber, as permitted by Novoheart’s proprietary technology.
The mini-heart models developed by Novoheart are contained in a jar and include a pressure transducer to measure changes in pumping capacity and electrical leads to control heart rate, explains Li. Novoheart has software that electrically mimics different disease states, in addition to adjustments it can make to hormones and drugs in the culture media.
The heart tissues are easily incubated for three to four months, says Li. “In fact, we believe they can be cultured for more than six months; we just haven’t done it yet.” That means the models could be used to look at the effects of therapies on chronic as well as acute heart conditions.
Pharmaceutical partners bring the needed disease biology expertise to the table, says Li. They also have large collections of samples from human patients, together with well-defined clinical profiles and genetic data. The partnership allows researchers to see how the model correlates to what happens in actual patients, as well as combine data in different ways to improve predictive performance.
Novoheart has published extensively on using the human heart-in-a-jar platform to measure the transcriptome, microRNA and the proteome, Li says, and will be doing likewise with AstraZeneca. “We want to see how much we can recapitulate what we observe in patients and also look at different omics data and see how similar they are to patient samples.”
The goal is to use the human models for screening drug candidates in hopes of identifying agents that can improve cardiac function before having to test them in actual patients, says Li. The technology can clone many hearts with the same genetic makeup to expedite testing across different subsets of patients.
Over time, Novoheart will be taking precision medicine to a new level with heart models “custom-matched to different ethnicities—a Chinese heart model, a Jewish heart model, you name it—and therefore address the big issue of genetic diversity,” Li adds.
Bridging the Gap
Novoheart’s pioneering heart-in-a-jar technology has been around for a few years, and several companies have since launched human heart tissue models, says Li. As was just announced, Novoheart signed an exclusive licensing agreement with the Harvard Office of Technology Development to combine its MyHeart Platform with Harvard University's tissue-engineered scale model of the heart ventricle and bioreactor technology to create an improved human heart model for the discovery of new therapeutics.
“This is a new market that we are trying to create, and I think we are starting to gain some pretty good traction,” says Li. “The platform is now being used to help drug developers discover new drugs and collect data on processes of the human heart”—and it is hoped that this will “bridge the longstanding gap” between drug safety data generated in preclinical research and clinical studies.
In the partnership arrangement with AstraZeneca and Pfizer, Novoheart retains ownership of the intellectual property for the heart-in-a-jar technology but the pharma company has first right to license it, says Li.
In addition to creating disease models for others, Novoheart has its own drug discovery program with several candidate compounds under development, Li notes. Earlier this year, Novoheart acquired Xellera Therapeutics, which will be building a Good Manufacturing Practice facility for generating clinical-grade gene vectors and human stem cell lines that can be used to make medicines for cardiac repair or regeneration.
The other, longer term aim of Novoheart is to “fine-tune” engineered heart tissue for subsequent transplantation into human patients. Progress continues in that arena as well, Li says, as is likely to be disclosed soon.