Sean Nygaard and colleagues have developed a new technique that may help to overcome one of the largest hurdles in gene therapy–the ability to generate a large pool of gene-corrected cells that would be effective in repairing or correcting injury and disease.
What’s more, in their method, the genetically corrected cells can repopulate in vivo.
To date, efforts to modify and deliver genetically modified cells to treat various disorders have required the delivery of thousands of cells, many of which don’t survive. This has limited the application of gene therapy, along with other concerns in the field, like the safety of the delivery vector.
Here, the researchers delivered a therapeutic gene along with a short hairpin RNA (shRNA) into liver cells in mice. The shRNA knocked down the level of a key enzyme, making the cells more resistant to a toxic drug called CEHPOBA. By treating a population of liver cells with the drug, the researchers ensured that only the gene-corrected cells went on to survive and repopulate the liver, producing higher than normal levels of the therapeutic transgene–in this case, a gene that prevents liver disease in mice.
This universal method of selection could be used to support cell-based treatments for neonatal metabolic liver diseases and genetic disorders, such as hemophilia B, say Nygaard and colleagues.
However, the technique could also be used to expand a therapeutic population of gene-corrected cells in many tissues that proliferate after injury, such as cells found in bone marrow, skin, or the intestine.
S. Nygaard, A. Barzel, A. Haft, A. Major, M. Finegold, M. A. Kay, M. Grompe. A universal system to select gene-modified hepatocytes in vivo. Science Translational Medicine, 2016; 8 (342): 342ra79 DOI: 10.1126/scitranslmed.aad8166