Pioneering Stem Cell Trial Halted Over Mutations in Stem Cells

A halt has been called to a pioneering stem cell clinical trial after genetic mutations were detected in the cells derived from one of the trial participants; cells that were to be used to treat the patient.

What makes this trial so unique is that it is the first to investigate if cells derived from induced pluripotent stem (iPS) cells can be used to treat disease. iPS cells are made from mature, adult cells that have been genetically engineered to transiently express four genes (Oct-4, Soc-2, Klf-4, and c-Myc), and then cultured in the laboratory in embryonic stem cell-type medium. This treatment kills many of the cells, but a fraction of them are developmentally regressed into a pluripotent stem-cell-like state. From this pluripotent state, the cells can be differentiated into almost any other type of cell in the body. Such differentiated cells can them be transplanted back into the body of the patient to replace diseased, dying cells.

In this trial, skin cells from trial participants were reprogrammed into iPS cells, which were then differentiated into retinal cells. Transplantation of these retinal cells could potentially interrupt or, perhaps even reverse, the damage caused by a disease called age-related macular degeneration, which leads to loss of vision and, potentially, blindness. The first patient in the trial, a 70-year-old woman, was treated in September, 2014, and is reportedly in good health.

Treatment of the second patient, however, has hit a snag. “A mutation was found in the cells before transplantation into the second patient, and this is something we took into account when we made the decision to suspend the study for the time being,” says trial leader Masayo Takahashi of the Riken Center for Developmental Biology in Kobe, Japan.

Analyses of the iPS cells made from skin cells taken from the second patient revealed six mutations. Three of these mutations consisted of deletion of particular genes, and the other three consisted of changes to genes, including one in an oncogene (a gene with the potential to cause cancer), although this one is linked with a low risk. The mutations were not detectable in the original skin cells, which suggests that they occurred as a result of the iPS-cell procedure. However, other work has shown that low-frequency mutations in the initial cells that are difficult to detect can become amplified in iPS cells derived from  that cell population.

“Either they were there at undetectable levels in the skin cells, or they were caused by the iPS cell induction process,” says Shinya Yamanaka of Kyoto University in Japan, one of the scientists who developed the iPS cell reprogramming technique. “However, the risk of carcinogenesis was considered low.”

Other factors that caused the trial to be halted are regulatory changes in Japan. Takahashi told the magazine New Scientist that the law now stipulates that in Japan only certain institutions can run stem-cell trials. Once the team has worked out how to accommodate these changes, they hope to resume work and test five more people using healthy, mutation-free skin cells from younger people.

“I think it’s an easily fixable problem if they go this route,” says Robert Lanza, chief scientist at Ocata Therapeutics in Marlborough, Massachusetts, which is also developing stem-cell therapies for age-related blindness.

Regardless, the discovery of mutations that could be related to the process by which iPS-cells are derived is troubling, and is a concern that stem cell scientists have had since iPS cells were first discovered. One of the benefits of stem-cell therapies is that the cells can multiply rapidly, which is also a characteristic shared by cancer cells.

But that similarity doesn’t necessarily mean cancer will develop. “It’s important to understand that even mutations in oncogenes don’t guarantee that cancer will result,” says Jeanne Loring of the Scripps Research Institute in La Jolla, California.

“It will be important to determine the source of the mutation before jumping to conclusions that reprogramming cells will always carry this sort of risk,” says Mike Cheetham of the Institute of Ophthalmology at University College London. “It will be important to determine the source of the mutation before jumping to conclusions”


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Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).