April 1, 2018 (Vol. 38, No. 7)

Therapeutics Based on Induced Pluripotent Stem Cells Are Nearing Clinical Trials

For those who advocate therapeutic applications of induced pluripotent stem cells (iPSCs), these are heady times. New funding flows are opening, regulations are undergoing some “streamlining,” and clinical trials are being planned.

Taken together, these developments justify optimism. Might they even inspire giddiness? Apparently not, if we may judge by the proceedings of the 2018 World Stem Cell Summit.

At this event, the presenters felt as optimistic as anyone about the future of iPSC-based therapies. Yet the presenters also acknowledged outstanding problems such as manufacturing bottlenecks and quality control issues. Buzzkills? Hardly. By discussing potential solutions to these problems, stem cell scientists show that they can celebrate progress responsibly. Until the first iPSC-based therapeutic is approved, the champagne bottles will stay corked. In the meantime, however, they’ll be chilling.

Encouraging Developments

Pluripotent stem cells, which include iPSCs and embryonic stem cells (ESCs), keep finding new applications. Well-studied applications include tissue and organ regeneration, disease modeling, and drug development. Going forward, pluripotent stem cells will be used to treat diseases such as age-related macular degeneration, Parkinson’s disease, and type 1 diabetes. In fact, iPSC-based therapeutics for these and other conditions will soon be evaluated in clinical trials in the United States. ESCs, which are already in clinical trials in the United States and abroad, are continuing through clinical development.

To ensure that stem cell therapies develop quickly, various parties are taking action. Developers are standardizing quality control measures. The FDA is developing manufacturing guidelines. And pharmaceutical companies are emphasizing data sharing.

Encouraging developments are also occurring on the legislative front. In 2016, the 21st Century Cures Act was passed, allocating $2 million to regenerative medicine research in 2017 and $10 million in 2018. The act enjoyed bipartisan support but still occasioned controversy. For example, some critics argue that the Act favors the interests of pharmaceutical companies over the safety of patients.

Emphasing the Act’s advantages, Joshua M. Hare, M.D., director of the Interdisciplinary Stem Cell Institute at the University of Miami Miller School of Medicine, told GEN that the legislation helped bring about a “pendulum shift.”

“The Act earmarked very specific dollars for the NIH to direct to regenerative medicine,” Dr. Hare explained. “The Act also requires matching funds to these grants, so it had a catalytic effect, whereby it brought more money out of the woodwork, and it’s really increased the activity significantly.”

The field, Dr Hare suggested, risked “languishing,” but now it exhibits renewed “enthusiasm” and “energy.” For instance, Dr. Hare and colleagues are generating clusters of cardiac precursor cells from human pluripotent stem cells. “I think you’re starting to see a lot of exciting things happen.”

iPSC Therapies Near U.S. Trials

No U.S. trials have begun using iPSCs, said Jeanne Loring, Ph.D., director of the Center for Regenerative Medicine at Scripps Research Institute. She noted that the the only iPSC trial is in Japan, for macular degeneration.

The struggles of iPSCs contrast with the successes of multipotent stem cells, which have been studied in the clinic for decades and have been approved for treatments. Even human ESCs been in clinical trials for several years in the United States.

The prospects for iPSC-based therapies, however, are improving. Such therapies are even approaching clinical trials in the United States. The top target disease for clinical study is macular degeneration, following by type 1 diabetes and Parkinson’s disease, said Dr. Loring.

Dr. Loring works on using iPSCs to treat Parkinson’s disease. She explained that the therapy involves taking skin cells from individual Parkinson’s patients and then reprogramming these cells so that they become pluripotent stem cells. Then the pluripotent stem cells are turned into dopamine neurons, which represent one of the cell types lost in Parkinson’s disease. Finally, the dopamine neurons can be transplanted. “Our trial using iPSCs for Parkinson’s disease is planned for 2019,” stated Dr. Loring.

Another application nearing the clinic is the transplantation of multilayer tissues derived from iPSCs. According to Dan Gincel, Ph.D., executive director of the Maryland Stem Cell Research Fund, companies have developed manufacturing processes for generating multilayer tissue sheets of appreciable depth, from a few millimeters to almost a full centimeter.

“You put one layer on top of the other,” he explained, adding that the idea is to create a multilayer sheet that can be transplanted at some point. “We’re not there with the transplants yet,” he admitted. He did confide, however, that he had heard we are “months away” from transplanting multilayer sheets of cells into humans, specifically layers of pancreatic cells. These sheets could be used to treat diseases such pancreatitis or type 1 or type 2 diabetes. He said that one study is in the “final stages” of approval for a clinical trial.

Mature dopamine neurons derived from human embryonic stem cells on laminin surface. [Karolinska Institutet]

ESC Therapies Keep Flowing

Human ESCs have been in U.S. clinical trials since 2009, when the FDA cleared Geron to begin a trial for spinal cord injury. Now, human ESCs are in clinical development for several diseases, many of which are also being targeted by iPSC-based therapies.

Several companies are involved: ViaCyte is evaluating two of its products for type 1 diabetes; Asterias Biotherapeutics is evaluating glial cell precursors for spinal cord injury; and Astellas Pharma, which recently acquired Ocata Therapeutics, is conducting trials for age-related macular degeneration.

“It is true that there are few trials using human ESC derivatives in the United States,” confirmed Dr. Loring. “There may be a few more soon.”

Outi Hovatta, M.D., Ph.D., professor of obstetrics and gynaecology at Karolinska Institutet, indicated that progress is made in Europe for age-related macular degeneration and Parkinson’s disease. She and her colleagues have manufactured retinal pigment epithelial cells (for age-related macular degeneration) and dopamine neurons (for Parkinson’s disease) from human ESCs according to good manufacturing practices.

According to Dr. Hovatta, a clinical trial to administer these ESC-derived retinal pigment epithelial cells is being planned at Karolinska Institutet. She added that “in the near future,” a European clinical trial for Parkinson’s disease could happen under the leadership of Professor Roger Barker at the University of Cambridge. In China, a clinical trial is already being done to evaluate human ESC-derived neural precursor cells for Parkinson’s disease.

Despite such advances, Dr. Gincel cautioned, the “most important” challenge ahead is the manufacture of pluripotent stem cells. Researchers, he said, will need to introduce several advances, such as better control of the environment and the ability to scaleup production.

In vitro differentiated retinal pigment epithelial cells derived from human embryonic stem cells. [Karolinska Institutet]

Experts Push for Quality Control

The FDA has begun increasing its oversight of stem cell therapies, and more regulations could be on their way. In November 2017, the FDA issued final and draft guidance on their approach to overseeing stem cell therapies and other regenerative medicine products. This came just a few months after a stem cell clinic in Florida was issued a warning letter for marketing unapproved stem cell therapies that were not made according to current good manufacturing practices.

Up next could be more rigorous quality control measures for pluripotent stem cells, which tend to develop oncogenic mutations. Using dopamine neurons as an example, Dr. Loring said, “Every single time that we make those cells from a patient, we have to be sure that those are dopamine neurons that are going to function when we put them back into their brains.”

“The idea is pretty straightforward,” she continued, “but the details are, I think, representative of what everybody is going to have to face, and that is, that we have to introduce quality control with every single stage.” Cells will need to be checked for genetic mutations at several steps.

This risk of tumor formation is in contrast to mesenchymal stem cells, which are multipotent and have a low risk of forming tumors. Despite the risk of tumor formation, Dr. Loring said that currently the FDA does not require genomic sequencing before administering pluripotent stem cell–derived cells into a person.

The FDA doesn’t know when—or if it will ever—require genomic sequencing, asserted Dr. Loring, who added, “We’re trying to change the FDA’s mind about what needs to be done, which is not something you want to take on lightly.”

“The groundwork for doing that is being laid out right now,” she declared. “We’re trying to be pioneers, and it is not easy to be a pioneer. My hope is that nothing terrible happens. I don’t want us to be learning what’s necessary because people suffer for not having checked something in advance.”

Diagram of the major quality control steps at which whole-genome sequencing and gene-expression profiling can be done to identify genetic mutations. [Scripps Research Institute]

Silos Must Fall

When Dr. Loring moderated a session at the 2018 World Stem Cell Summit about the advances in pluripotent stem cells, she insisted on this take-home message: “We need to break down silos.”

The silos Dr. Loring would like to eliminate are informational and disciplinary barriers that slow innovation. She explained that all the people studying stem cells, including scientists on both sides of the academic/commerical divide, should find ways to share their information; otherwise, they will waste a lot of time and effort reinventing things.

“It’s really just a matter of us sharing the information and being willing to come up with standards that we all agree on,” she maintained. “And that’s just not easy, but I think it’s going to be necessary.”

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