On February 18, 2019, The Asahi Shimbun reported, “Ministry [of Health, Labor and Welfare in Japan] OKs 1st iPS [induced pluripotent stem] cell therapy for spinal cord injuries.” This announcement disseminated at a press conference has been viewed as an exciting clinical trial on the use of stem cells to treat spinal cord injury. However, caution is warranted here, for at least three reasons: the uncertainty of the stem cell type to be used in their clinical trial, the safety of transplanting stem cells into humans, and the responsibility of scientists and the press to communicate clearly the benefits and risks of the stem cell treatments, especially to desperate patients who would seek such unproven treatments.
First, reports of the announcement by the lead scientist Hideyuki Okano of Keio University School of Medicine provide no indication where this trial is described or registered. It is of concern that it is not listed at clinicaltrials.gov or Japanese registries including UMIN Clinical Trials Registry (UMIN-CTR) and the Japan Medical Association Center for Clinical Trials (JMACCT).
Second, Okano’s group reported in a study on mice that transplanted human iPSC-derived neural stem/progenitor cells (NSPC) retain unwanted proliferative characteristics, which they attributed to karyotype abnormalities. To protect against these abnormalities, Okano and colleagues have developed a “Fail-Safe System against Potential Tumorigenicity after Transplantation of iPSC Derivatives,” to quote the title of their report. Based on their results, they stated in the study that their technique “may serve as an important countermeasure against post-transplantation adverse events in stem cell transplant therapies.” However, they also caution that “a number of problems . . . need to be resolved, and at present [the Fail-Safe System] is still not suitable for clinical application.”
Thus, the question remains whether their approach—based on an inducible suicide gene introduced to kill the cells in case of abnormal growth—will be used in these clinical trials, and the expected safety profiles of the cells used in their studies remains unclear. Even small tumors in the spinal canal can be particularly dangerous considering there is little room for these cells to grow and they can compress the cord causing paralysis.
Human embryonic stem cells were first isolated and maintained in culture in 1998 and yet in the past 20-plus years, positive clinical outcomes using stem cells has been extremely limited due to many safety issues, including uncontrolled cell proliferation, uncontrolled cell differentiation, and tumorigenesis. In addition, in many situations, the transplantation of stem cells in vivo results in massive cell death of these cells within days to weeks of injection.
The third issue is communication. Okano said during the press event that it will take a year to confirm the treatment is safe and effective, which sounds quite assuring and encouraging given his outstanding accomplishments in preclinical research showing efficacy of iPSC-NSPC in mammals and most recently in nonhuman primates. However, The Asahi Shimbun article also noted, “Given that tumors are a potential side effect of the treatment using iPS cells, and therefore a major cause of concern, the team put priority on safety by deciding to use relatively small amounts of cells: 2 million cells for each transplantation.” One needs to be concerned that this relatively low dose is insufficient for human therapy considering it is only four times the dose that was effective in the mice, as reported in Okano’s study.
The excitement of the press release may be misinterpreted by patients, who may think that now is the time to treat human spinal cord injury with stem cell transplants. With difficulties getting admitted to legitimate sub-clinical trials, could this hype for hope lead poorly informed patients to seek out other “stem cells” to treat their spinal cord injuries or other conditions? We must avoid anything that may promote “medical tourism” to unapproved interventions.
The fact that there are more than 700 “stem cell clinics” advertised in the United States alone highlights the desperation of so many patients with terminal illnesses seeking unapproved or unproven therapies. There are no studies documenting the therapeutic successes of these clinics and some of their patients have developed serious side effects. Scientists and the press must ensure an ethical and realistic presentation and communication of new and potentially exciting discoveries and caution readers about the realities of initial clinical trials.
John D. Loike, a professor of biology at Touro College and University Systems, writes a regular column on bioethics for The Scientist. Martin Grumet is a professor of Cell Biology & Neuroscience, associate director of WM Keck Center for Collaborative Neuroscience, and director of the Stem Cell Research Center at Rutgers.