Lawrence Goldstein, Ph.D., reprograms iPSCs to create cell lines that carry “the unique genetic constitution of whatever person donated the skin cells. So if it’s a person with hereditary Alzheimer’s disease [AD], you can then make human brain cells—human neurons—in a dish that have the genetic change that caused AD, and study what’s different about those neurons from normal.”
Similarly, his lab also investigates neurons made from the skin of patients with sporadic AD. Sixty to eighty percent of the risk for developing the disease comes from genetic variation, and so it is likely that these nouveau brain cells will manifest some of the same biochemical changes that caused AD in their donors.
“Can you analyze that and figure out what’s going on?” the University of California–San Diego distinguished professor asked. If so, “that lets you do experiments on mechanism: What’s going wrong? Can you treat it with drugs? Can you look for drugs? And all the rest.”
They purified cultures by flow cytometry to greater than 90% neurons, “enabling a much more precise biochemical evaluation,” Dr. Goldstein explained. Lines made from the hereditary AD donors and from one of the two sporadic AD donors were found to have significantly higher levels of various pathological AD markers, including amyloid-β and phospho-tau; they were able to pharmacologically block the effect on phospho-tau expression.
He has also been using the same stem cell technologies to study common variants associated with sporadic AD, regardless of whether the donor has any clinical signs of disease. “I will talk about a project at this meeting to nail down what the molecular behavior is that is different in people who have a particular variant in the human population.”
Stanford University School of Medicine’s Joseph Wu, M.D., Ph.D., agrees with this philosophy. He takes issue with the pharmaceutical industry’s reliance on Chinese hamster ovary (CHO) cells—transgenic for a single heart ion channel (HERG), easy to grow, but not even able to beat—being used for cardiotoxicity drug screening: “The human heart has over 15 major channel genes,” he pointed out. “Relying on CHO cells expressing HERG channels can lead to many false positive and false negative hits.”
To circumvent the problem his lab has derived cardiomyocytes from human skin cells (hiPSC-CMs). “The cardiac cell that we obtain beats on a dish so we can measure several parameters. Does the cardiac cell beat faster or slower after exposure with drugs? Does it beat stronger or weaker? Does the drug cause arrhythmia in different patient cohorts? So we have a variety of readouts that are very similar to the human heart physiology which allows us to what’s the effect of the drugs on these cells in a dish,” not just on the HERG channel, noted Dr. Wu.
Many drugs can be safe for the majority of the population, but harmful or fatal for those with certain abnormalities or genetic backgrounds. Wu has been creating disease-specific hiPSC-CMs from patients with various hereditary cardiac disorders. By using these population-specific cells to screen drug candidates, such negative interactions may be identified and avoided while potentially rescuing otherwise valuable pharmaceuticals.
Dr. Wu sees iPSC-derived cell testing as playing a major role in the future, and “not just for the heart. People will make patient-specific models for brain diseases, for hepatic metabolism, for diabetes, and try to show that this can be useful for predicting drug response.”
With the pace of current technology, in 5–10 years CROs will do drug testing on panels derived from 1,000 people of various genetic and ethnic backgrounds, he predicted. And in 20 years, “you should be able to take a patient’s skin or blood, make these iPSC-derived cells on a dish or in 3D organoids, and use them as phenotype readouts along with patients’ genotype data for personalized medicine that is safer and more predictive.”