Gene therapy offers great promise for treating genetic disorders and in repairing or correcting injury and disease. However, efforts to modify and expand the pool of gene-edited cells to reach therapeutic levels have proved challenging to date. Current methods are not only time consuming and expensive, but also present a risk to the patient. Now a team of researchers led by Sean Nygaard, B.S., M.Div., senior research associate in the Markus Grompe Lab at OHSU’s Oregon Stem Cell Center, has developed a new technique that may help overcome this hurdle. In the June 8 edition of Science Translational Medicine, Nygaard details a new platform technology that selects for gene-edited cells in vivo, allowing therapeutic levels of healthy cells to survive when subjected to toxic drugs such as those used in chemotherapy.
In this study, Nygaard, Markus Grompe, M.D., and colleagues injected cells that had been genetically modified to be resistant to a toxic drug, CEHPOBA, into the livers of live mice. They then treated the animals with CEHPOBA or saline for several weeks. They found that those treated with the drug saw an order-of-magnitude increased trans-gene expression compared with the mice treated with saline. So by treating a population of liver cells with the drug, the researchers ensured that only the gene-corrected cells survived and repopulated the liver.
This universal method of selection can be used to support cell-based treatments for genetic disease such as hemophilia B and metabolic liver diseases, or extended to any tissue that proliferates after injury, including the bone marrow and skin, Nygaard’s study found.
Nygaard was first author on this paper, “A universal system to select gene-modified hepatocytes in vivo.” Grompe was corresponding author. Coauthors are Adi Barzel, Ph.D. formerly at Stanford University School of Medicine (currently at Tel Aviv University), Annelise Haft, senior research assistant in the Grompe Lab, Angela Major, Baylor College of Medicine, Milton Finegold, M.D., Baylor College of Medicine, Mark A. Kay, M.D., Ph.D, Stanford University School of Medicine.