Compensating for a Defective Gene: A New Potential Treatment for Heart Failure
by Adrienne Mueller, PhD
June 9, 2021
When Your Genes Hurt Your Heart
Calcium plays a crucial role in our hearts. Our heartbeat—heart contractions that pump our blood—is caused by changes in calcium in our heart muscle cells. Therefore, the regulation of calcium—how much is available at any given time—is extremely important for our hearts' healthy function. Phospholamban is a tiny protein that plays an important role in regulating the amount of calcium and hence the force of heart contractions. When born with a genetic error in your phosopholamban gene, your heart develops dilated cardiomyopathy, which is characterized by weakened heart muscle and eventual enlargement of the heart, arrhythmia, and, too frequently, heart failure and death. Dilated cardiomyopathy is the leading cause of heart failure and inherited forms account for up to a third of cases. The specific phospholamban mutation in this study is associated with heart failure, arrhythmias, and sudden cardiac death. The mechanism behind why this mutation causes this unfortunate condition is unknown, and there are no specific therapies.
How Your Heart Responds
Postdoctoral fellows Dries Feyen, PhD, and Isaac Perea-Gil, PhD, (Mark Mercola and Ioannis Karakikes labs) led a study recently published in Circulation that shed light on how the phosopholamban mutation causes heart disease. In collaboration with researchers from the Netherlands, and support from the Phospholamban (PLN) Foundation and the Foundation Leducq, the investigators harnessed stem cell technology to recreate the patients' heart muscle cells in the laboratory. They also applied genome editing tools to correct the mutation. Comparing the corrected versus the patient heart cells, the defective contractility caused by the mutation was clearly evident. Moreover, they discovered a clue that might lead to a therapy: the mutant heart muscle cells had activated the cellular "unfolded protein response pathway." Thus, the investigators could use stem cell technology to reproduce this disorder in vitro and determine specific changes in gene expression in heart muscle cells with mutant phospholamban. "This research illustrates how iPSC disease modelling can facilitate discovery of mechanism-based therapeutics for heart disease," says senior author Ioannis Karakikes.
The researchers next asked: is the activation of the unfolded protein response pathway actually causing the contractility deficit—or is it a means by which the heart cells were trying to compensate for their defective phosphlamban? Feyen and Perea-Gil, et al, tested both hypotheses. When they blocked the unfolded protein response, they found that the contractility defect became even worse. However, when they used a small molecule to activate the pathway, they showed that the contractility deficit in both 2D and 3D engineered heart tissue improved. The authors therefore demonstrated that the unfolded protein response pathway exerts a modest protective effect in the diseased heart cells and that further activation with a small molecule could restore most of the contractile function. Thus, specific activation of this pathway might be a new therapeutic avenue to treat phospholamban mutant dilated cardiomyopathy and prevent heart failure.
Additional Stanford Cardiovascular Institute-affiliated authors who contributed to this study include Alexandra A. Gavidia, Jennifer Arthur Ataam, Ting-Hsuan Wu, Nirmal Vadgama, Michelle Vu, Prashila L. Amatya, Maricela Prado, Yuan Zhang, Logan Dunkenberger, and Karim Sallam.