By Holly Ober
Creating a model of atrial fibrillation with live human heart cells on a chip is the goal of a new $6 million, five-year grant to Professor Steven George at the UC Davis Department of Biomedical Engineering and colleagues at Washington University in St. Louis.
Atrial fibrillation is an irregular heartbeat caused when the heart’s upper chambers beat chaotically and out of sync with the lower chambers, leading to a variety of health problems including stroke and death. Nearly one in ten people over the age of 65 suffer from atrial fibrillation at a cost of around $6 billion.
Conventional treatment for atrial fibrillation involves drugs that target heart muscle proteins that allow electrical current to flow. But the drugs themselves can cause an irregular heartbeat, and act not only on the atria of the top chamber but also on the lower chambers of the heart (ventricles). Arrhythmia in the ventricles is a very serious conditions that can lead to sudden death.
Surgery to treat atrial fibrillation is successful in only a small percentage of patients. Thus, new approaches are necessary as our population ages.
Model atrial fibrillation on a chip, then treat it with gene editing
George and his collaborators plan to grow atrial tissue from patients’ stem cells, then alter these cells using CRISPR technology (“gene editing”) so that they conduct electricity in a pattern resembling that seen in atrial fibrillation.
Once they have developed this artificial atrial fibrillation on a chip, they will attempt to reverse the pattern with gene editing delivered by a modified virus that only targets the atria.
“Heart muscle cells ‘connect’ to each other to allow electrical current to pass between them, and these connections are altered in patients with atrial fibrilllation. We can’t reproduce true atrial fibrillation on our chip, but we can reproduce the features of how cells communicate electrically that predispose a person to the condition, and that’s what we’re trying to do in this new project,” George said.
The stem cells will be obtained from white blood cells or skin cells, and treated to encourage them to form the heart muscle cells found in the atria. The cells that make up the ventricle and the atria are so similar that growing only atrial heart muscle cells is a delicate task, but George’s lab has already done some initial work in this area, and he believes they will succeed.
George’s strategy to treat atrial fibrillation targets “upstream” proteins that orchestrate production of the membrane ion channel proteins that control electrical activity in the atria. If successful, the treatment would be reversible and not permanently change the “genetic code” of the patient.
The project is part of a 5-year NIH program dubbed “Tissue Chips 2.0”, which funds research into models of disease on laboratory chips. Co-principal investigators on the project are Stacy Rentschler, MD, PhD, and David Curiel, MD, PhD, both of whom are at Washington University St. Louis. The tissue engineering and lab-on-a-chip work will be done at UC Davis, while the gene therapy and ex vivo testing will be done at Washington University in St. Louis.
Holly Ober writes for the UC Davis Department of Biomedical Engineering.