First human trials of embryonic stem cell-based therapies head to the clinic

On January 3, stem cell therapeutics company Advanced Cell Technology (ACT) announced it had received approval from the US Food and Drug Administration to kick off a Phase I/II clinical trial using the company's retinal epithelial cells (RPE). The cells would be used to treat dry age-related macular degeneration (AMD), a progressive vision impairment affecting some 15 million Americans.

It's always good news for a company when the FDA clears an investigational new drug application. What made this particular announcement interesting was the source of the biologic agent: ACT would be treating a dozen patients with between 50,000 and 200,000 cells derived from human embryonic stem cells. These cells will be injected into the subretinal space of patients' eyes, where it is hoped they will "restore visual acuity" by activating dormant photoreceptors, says CEO Gary Rabin.

Preclinical data, Rabin says, look promising. "In our animal studies, we saw our ability to take rats and mice that were otherwise on their way to being completely blind, and reverse their vision loss to the point that we had restored their visual acuity to 70% that of a healthy animal," he says.

The question is, will positive outcomes in animal models translate to human subjects? And more importantly, is the therapy safe?

ACT's AMD trial actually is the third hESC-based trial approved by the FDA. In November, FDA green-lit the company's IND for using its RPE cells to treat Stargardt’s Disease, a genetic form of juvenile macular degeneration. The company hopes to begin both trials in May, Rabin says. But Geron Corp. has the honor of actually initiating the first study, officially enrolling its first patient in a trial to treat spinal cord injury with hESC-derived oligodendrocyte progenitor cells (GRNOPC1) in October.

"I think that is a momentous milestone," says George Daley, Director of the Stem Cell Transplantation Program at Children's Hospital Boston and Executive Committee member of the Harvard Stem Cell Institute, "because it required enormous, I would even say Herculean effort to qualify those cells to achieve a certain level of comfort that they were safe enough to put into humans."

And it is one, Daley adds, that should "pave the way for others to follow."

The Geron trial, with sites in California, Georgia, Illinois, and Pennsylvania, involves up to 10 patients with so-called mid-thoracic "complete" spinal cord injuries – paraplegic injuries induced by a fall or car accident, for instance. The cells will be administered in a single injection of 2 million cells within one to two weeks of injury, under general anesthesia, by a trained neurosurgeon using a custom-built "syringe positioning device," says Jane Lebkowski, CSO of the company's regenerative medicine section.

Geron's preclinical data suggest the cells have three separate, yet interrelated activities, Lebkowski says: producing neurotrophic factors that can prevent cell death and induce cell growth; remyelinating myelin-depleted cells in the damaged area; and inducing vascularization. "I don't think it's any one mechanism," Lebkowski says; all three seemingly contribute to the cells' therapeutic effect.

How much repair these cells can produce, of course, is an open question. According to Aileen Anderson, a spinal cord injury expert at the University of California, Irvine, patients are likely to see at best modest gains. It's not like paraplegics are likely to simply get up and start walking, she says. But the value of even subtle improvement should not be underestimated, she explains. Restoration of trunk stability or bladder control in a paraplegic, for instance, can make patients more self-sufficient, restore dignity, and decrease medical costs (for instance, by reducing pressure sores and other complications). The same is true for blindness. "There's a big difference between being able to see shadow and not," she says.

That said, efficacy is not a primary endpoint of these studies; as Phase I trials, their goal is to assess safety.

Among the concerns: hESCs can differentiate into any type of cell in the body, but they can also form tumors. Thus, it was important to demonstrate to the FDA that no pluripotent cells will actually make it into the body. "Just saying I can turn embryonic stem cells into RPE cells, yes that's a great feat of science. But making sure that every single cell I inject is in fact an RPE cell, that's a massive leap forward," says Rabin.

"Adult" stem cells don't have that problem. StemCells, Inc. announced March 14 the initiation of a Phase I/II clinical trial of its human neural stem cells in spinal cord injury, having received Swissmedic authorization in December to conduct the trial in Switzerland. These tissue-derived or adult stem cells, called HuCNS-SC® cells, are "the 'parent cell' of the brain," explains Stephen Huhn, vice president and head of the CNS program at StemCells – in vivo, these cells can differentiate into astrocytes, oligodendrocytes, and neurons. But they otherwise are lineage-restricted; as a result, the risk of inappropriate and uncontrolled cell growth is reduced.

According to Huhn, the company's experience in two previous Phase I clinical trials, accrued over the past four-and-a-half years and counting, has been positive. The company has transplanted between 500 million and 1 billion HuCNS-SC cells directly into the brains of 10 pediatric patients with advanced neurodegenerative disorders. (By comparison, Geron intends to test 2 million cells in its spinal cord injury trial.) "We think we have a favorable safety profile, and one that is based on a significant cell dose into the central nervous system," he says.

Another issue is that, animal studies notwithstanding, nobody really knows how the differentiated cells will behave once injected in humans, nor how the immune system will respond. Though both the spinal cord and eye are relatively "immunoprivileged" locations, both Geron's and ACT's therapeutic regimens include immunosuppressants, at least initially. But, will the cells engraft as expected? Will they repair the tissue in the same way? "The catch-22 is that we don't have a perfect animal model where we can ask that question," says Anderson, who helped run the preclinical program for HuCNS-SC.

According to Lebkowski, the intense scrutiny accompanying these first-in-kind trials adds tremendous pressure to dot every i and cross every t. "Oh, god, I mean, it's huge," Lebkowski says, "and it's something that we take very, very, very seriously." Nobody wants stem cell therapeutics to suffer the same setback as the gene therapy field following the death in 1999 of 18-year-old Jesse Gelsinger during a trial at the University of Pennsylvania.

But, says Lebkowski, "You can never make something 100% safe." To stack the deck, Geron has developed what she calls "a risk-mitigation strategy," a combination of biochemical, imaging, and neurological screens and third-party oversight intended to catch problems as early as possible. Geron's patients will, among other things, undergo nine MRI scans in the first year, Lebkowski says. And they will be monitored, she adds, for 15 years "to make sure that nothing untoward has happened" as a result of the treatment.

Whatever happens, says Larry Goldstein, Director of the Stem Cell Program and an HHMI Investigator at the University of California, San Diego, these initial Phase I trials should be informative. "If there were significant clinical improvement in the absence of obvious safety concerns, that would be a huge step forward," Goldstein says. "But even if there are safety concerns that are identified, that's a step forward, because you can't solve problems you don't know about."