Cutting-edge stem cell therapy proves safe, but will it ever be effective?

It’s official: The first use of induced pluripotent stem (iPS) cells in a human has proved safe, if not clearly effective. Japanese researchers reported in this week’s issue of The New England Journal of Medicine ( NEJM ) that using the cells to replace eye tissue damaged by age-related macular degeneration (AMD) did not improve a patient’s vision, but did halt disease progression. They had described the outcome at conferences, but publication of the details is an encouraging milestone for other groups gearing up to treat diseased or damaged organs with the versatile replacement cells, which are derived from mature tissues.

This initial success “is pretty momentous,” says Alan Trounson, a stem cell scientist at the Hudson Institute of Medical Research in Melbourne, Australia. But the broader picture for iPS therapies is mixed, as researchers have retreated from their initial hopes of creating custommade stem cells from each patient’s tissue. That strategy might have ensured that recipients’ immune systems would accept the new cells. But it proved too slow and expensive, says Shinya Yamanaka of Kyoto University in Japan, who first discovered how to create iPS cells and is a co-author of the NEJM paper. He and others are now developing banks of premade donor cells. “Using stocks of cells, we can proceed much more quickly and cost effectively,” he says.

Even so, “clinical work is progressing more quickly than I had expected,” says Yamanaka, who did his groundbreaking work just a decade ago. His collaborator on this trial, Masayo Takahashi of the RIKEN Center for Developmental Biology in Kobe, Japan, had a head start. An ophthalmologist, Takahashi was familiar with the ravages of AMD, a condition that progressively damages the macula, the central part of the retina, and is the leading cause of blindness in the elderly.

Takahashi started investigating treatments for AMD in 2000, a time when the only cells capable of developing into all the tissues of the body had to be extracted from embryos. But she was stymied by immune reactions to these embryonic stem (ES) cells. When Yamanaka announced that he could induce mature, or somatic cells, to return to an ES cell–like state, Takahashi quickly changed course to develop a treatment based on iPS cells.

Her team finally operated on the first patient, a 77-year-old Japanese woman with late-stage AMD, in September 2014. They took a sample of her own skin cells, derived iPS cells, and differentiated them into the kind of retinal cells destroyed by the disease. A surgeon then slipped a small sheet of the cells into the retina of her right eye.

An operation on a second patient was called off because a number of minor genetic mutations had crept into his iPS cells during processing, and uncontrolled growth—cancer—has been a worry with such cells. “These changes do not directly induce cancer, but we wanted to make safety the first priority,” Yamanaka says. Also, Takahashi says, AMD drugs had stabilized the patient’s condition so there was no urgency in subjecting him to the risks of surgery, which include hemorrhaging and retinal damage.

Immediately after surgery the first patient reported her eyesight was brighter. Takahashi says the surgery halted further deterioration of her eye, even without the drug injections still being used to treat her other eye, and there were no signs of rejection of the graft as of last December.

Clinical work is progressing much more quickly than I expected. Shinya Yamanaka, Kyoto University

The result is “a proof of principle that iPS cell–based therapy is feasible,” says Kapil Bharti, a molecular cell biologist at the U.S. National Institutes of Health’s National Eye Institute in Bethesda, Maryland, who is also developing iPS cells for treating AMD. Takahashi says once her team gains more experience with the technique they will extend it to patients with earlier-stage AMD in an effort to preserve vision.

Last month, Takahashi won approval to try the procedure on another five patients with late-stage AMD. But this time, instead of using iPS cells derived from each patient, the team will draw on banked cells from a single donor. “It takes time to create iPS cells, and a lot of time for the safety evaluation,” Yamanaka says. It is also costly, at nearly $900,000 to develop and test the iPS cells for the first trial, Takahashi adds.

Using donor cells to create the iPS cells will make it more difficult to ensure immune compatibility. But Yamanaka says that donor iPS cells can be matched to patients based on human leukocyte antigen (HLA) haplotypes—sets of cell-surface proteins that regulate immune reactions. HLA-matched cells should require only small doses of immunosuppressive drugs to prevent rejection, Takahashi says—and perhaps none at all for transplantation into the “immune-privileged” eye.

Kyoto University’s Center for iPS Cell Research and Application, which Yamanaka heads, has been developing an iPS cell bank. Just 75 iPS cell lines will cover 80% of the Japanese population through HLA matching, he says. Trounson, a past president of the California Institute for Regenerative Medicine, a stem cell funding agency, says banked iPS cells have advantages. Donor iPS cells may be safer than cells derived from older patients, whose somatic cells may harbor mutations. And Jordan Lancaster, a physiologist at the University of Arizona in Tucson, likes the speed of the approach. He is devising patches for heart failure patients based on iPS-derived myocardial cells that will be “premanufactured, cryopreserved, and ready to use at a moment’s notice.”

Patient-specific iPS cells will still have clinical uses. For one thing, Bharti says it will be difficult for cell banks to cover all HLA haplotypes. And a patient’s own iPS cells could be used to screen for adverse drug reactions, says Min-Han Tan, an oncologist at Singapore’s Institute of Bioengineering and Nanotechnology, who recently published a report on the approach.

Other human trials are not far behind. Yamanaka says his Kyoto University colleague Jun Takahashi (Masayo Takahashi’s husband) will launch trials of iPS-derived cells to treat Parkinson’s disease within 2 years. Bharti hopes to start human trials of iPS cells for a different type of macular degeneration next year. And as techniques for making and growing iPS cells improve, researchers can contemplate treatments requiring not just 100,000 cells or so—the number in Takahashi’s retinal sheets—but millions, as in Lancaster’s heart patches.

As clinical use approaches, Takahashi cautions that researchers need to keep public expectations realistic. For now, iPS treatments may help but won’t fully reverse disease, she says. “Regenerative medicine is not going to cure patients in the way they hope.”