Their first step was to generate induced pluripotent stem cells — or iPS cells, which can develop into any type of cell — from cells obtained from the patient’s blood. The iPS cells were differentiated into cardiomyocytes, or heart cells that actually beat spontaneously in the culture dish like a heart. They had the exact genetic makeup of the patient, including the variant of the KCNH2 gene.
You can generate a patient’s heart cells in a dish and study them just from a simple blood sample.
These kinds of cells, which are grown in the lab, are what researchers refer to as a “disease in a dish” or a “patient in a dish.” They can be used for a variety of tests, including many that may not be feasible to conduct on patients themselves. The researchers also developed heart cells from a healthy patient for comparison.
“An advantage of generating patient-specific iPS heart cells is that you don’t have to use any invasive procedures on the patient to get them,” Garg said. “You can generate a patient’s heart cells in a dish and study them just from a simple blood sample.”
The researchers used a gene-editing tool known as CRISPR to correct the mutation, a faulty nucleotide in the KCNH2 gene, and also to introduce the same faulty nucleotide into the healthy control gene.
Tests of the heart cells with the mutation showed the hallmark features of long QT syndrome, including electrical disturbances that delay heartbeats and a mild propensity for arrhythmias compared with the cells from the healthy patient, the study said. These results did not show up in tests on the cells in which the mutation was turned off or in unaltered cells from the healthy patient.
The results confirmed that the patient did have a mild case of long QT syndrome, the study said.
In another study published recently in Circulation and also led by Wu, the researchers used the same genetic-editing tools and stem cell technology to determine that a variation of uncertain significance, which doctors worried could have been an indication of a dangerous heart condition known as hypertrophic cardiomyopathy, was actually benign.
“We were able tell the patient not to worry about it,” Wu said.
The success of using these same methods to determine whether two different patients were at risk for two completely different diseases suggests that this platform is a promising risk-assessment tool for variants of uncertain significance in general, Wu said. “The results of these studies are particularly exciting to me because we used precision health methods to address an unmet need for a patient,” he said. “This means we now have the ability to go deeper and tell a patient what a variant of uncertain significance means.”
The work is an example of Stanford Medicine’s focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill.
The study’s other Stanford authors are instructors Angelos Oikonomopoulos, PhD, and Yingxin Li, PhD; former postdoctoral scholar Haodong Chen, PhD; postdoctoral scholar Chi Keung Lam, PhD; Karim Sallam, MD, clinical assistant professor of cardiovascular medicine; and Marco Perez, MD, assistant professor of cardiovascular medicine.
Researchers from the University of Utah also contributed to the study.
Stanford’s Department of Medicine also supported the work.