Stanford University School of Medicine researchers grew heart muscle cells and used them, along with CRISPR, to predict whether a patient would benefit or experience bad side effects to specific therapeutic drugs
What would it mean to pathology groups if they could grow heart cells that mimicked a cardiac patient’s own cells? What if clinical laboratories could determine in vitro, using grown cells, if specific patients would have positive or negative reactions to specific heart drugs before they were prescribed the drug? How would that impact the pathology and medical laboratory industries?
We may soon know. Researchers at Stanford University School of Medicine (Stanford) have begun to answer these questions.
May Be Feasible for Clinical Laboratories to Use Pluripotent Stem Cells for Assays
1) Whether a patient would benefit from a specific therapeutic drug; and
2) The likelihood that the patient might have a negative reaction or bad side effect from that drug.
“Thirty percent of drugs in clinical trials are eventually withdrawn due to safety concerns, which often involve adverse cardiac effects. This study shows that these cells serve as a functional readout to predict how a patient’s heart might respond to particular drug treatments and identify those who should avoid certain treatments,” said Joseph Wu, MD, PhD, in the Stanford press release. Wu is Director of Stanford’s Cardiovascular Institute and a Professor of Cardiovascular Medicine and Radiology.
The researchers believe their discovery could become a form of diagnostic and prognostic testing performed by pathologists and clinical laboratories if it passes further clinical trials.
Heart Muscle Made from Stem Cells, Study Advances Precision Medicine
The iPS cells are stem cells created in a lab, usually from a person’s skin sample, and then induced into becoming cells from other parts of the body. Heart muscle cells made from iPS cells mirror the expression patterns of key genes in the donor’s native heart tissue. This means the cells can be leveraged to predict a patient’s likelihood of experiencing drug-related heart damage, according to the Stanford release.
The Stanford study also advanced precision medicine. It combined genetics, large-scale data research, and individualized testing to determine the best treatments for patients, noted an article in United Press International (UPI).
Researchers were motivated by a need to understand individual susceptibility to drug-induced cardiotoxicity, to improve patient safety, and to prevent drug attrition, according to the Stanford study, which was published in the research journal Cell Stem Cell.
“Human iPS cells enable the study of pharmacological and toxicological responses in patient-specific cardiomyocytes and may serve as preclinical platforms for precision medicine,” the authors noted in the study summary.
Furthermore, the researchers’ idea could have implications for medical conditions beyond cardiomyopathy, noted an article in LabRoots.
Cardiomyopathy is a disease of the heart muscle that affects millions of people worldwide each year.
Testing Tissues in the Stanford University Research Lab
Here’s how the research progressed, according to the Stanford press release:
• Matsa, Wu, and their colleagues created heart muscle cells, or cardiomyocytes, from iPS cells taken from seven people not known to be genetically predisposed to cardiac problems;
• They sequenced the RNA molecules made by the heart muscle cells to learn which proteins the cells were making, and by how much;
• They then compared the results within individuals—looking at the gene expression patterns of cardiomyocytes derived from several batches of iPS cells from each person—as well as among all seven study subjects.
• They also investigated how the cardiomyocytes from each person responded to increasing amounts of two drugs: Rosiglitazone (marketed as Avandia by GlaxoSmithKline), which is sometimes used to treat Type 2 diabetes; and Tacrolimus (marketed as Prograf by Astellas Pharma), which serves as an immunosuppressant to inhibit the rejection of transplanted organs. Each of the two drugs has been associated with adverse cardiac effects in some people, but it has not been possible to predict which patients will experience heart damage.
“Gene expression patterns of the iPS cell-derived cardiomyocytes from each individual patient correlated very well,” said Elena Matsa, PhD, Stanford Instructor, Cardiovascular Institute, and the study’s lead author. “But there was marked variability among the seven people, particularly in genes involved in metabolism and stress responses. In fact, one of our subjects exhibited a very abnormal expression of genes in a key metabolic pathway.”
Gene Editing Reveals Drug Response Information
Enter the Clustered Regularly Interspaced Short Palindromic Repeats, or CRISPR (pronounced crisper), gene editing technology. CRISPR technology has advanced the study and practice of genetic medicine.
Researchers could not pinpoint a specific gene mutation responsible for abnormal cardiomyocyte response. But they did identify a metabolic pathway that influenced Rosiglitazone’s response.
They corrected the abnormality using CRISPR-Cas9 (a simplified version of the CRISPR/Cas system). This genome editing technique enables researchers to edit parts of the genome by removing or changing in some manner the DNA sequence, according to yourgenome, an information website dedicated solely to DNA, genes, and genomes.
The results? The Stanford researchers reported boosting a gene expression in the pathway, restoring normal function, and prompting a response to Rosiglitazone that was consistent to that of the other subjects’ cardiomyocytes.
Clinical Laboratories Become Even More Integral to Cardiac Diagnosis and Treatment
Can iPS-derived cardiomyocytes reliably replicate human heart tissue? Researchers were not sure. So, they created iPS cells from another three people who had heart biopsies or transplants.
They then compared the cells made in the clinical laboratory with the gene native cells and found that they were similar in many significant ways.
In the end, cardiomyocytes derived from human iPS cells correlated with patient participants in the Stanford study. And, most importantly, the study revealed a potential ability to test drugs for adverse reactions and improve treatment for millions of people with cardiomyopathy. Should additional research confirm these findings, it could provide medical laboratories with a new approach to improving diagnosis and therapeutic selection for patients with heart disease.
—Donna Marie Pocius