Islets in the Stream: Could Stem Cell Technology Be an Eventual Cure for Type 1 Diabetes?

Recent studies have shown how stem cell-derived therapies have the potential as a renewable source of insulin-producing pancreatic islet cells. Promising as these results are, could stem cell technology eventually lead to a cure for diabetes as well as impacts well beyond endocrinology?

Last December, two papers appeared in Cell Stem Cell and Cell Reports Medicine, touting positive preliminary results of an ongoing, first-in-human Phase 1/2 study demonstrating that stem cell-derived therapy can produce insulin in people with severe type 1 diabetes.

The Cell Stem Cell paper reports on findings from 15 patients who were implanted with ViaCyte’s PEC-Direct product, comprising pancreatic endoderm cells (PEC-01) contained within macroencapsulation devices that allow for direct vascularization of the cells designed for subcutaneous placement.  This part of the trial took place at the University of British Columbia (UBC) and Vancouver Coastal Health (VCH) in Canada. Six months after implantation, researchers observed that the cells had matured into insulin-producing islet cells. They also detected a rise in C-peptide levels after patients ate a meal, indicating functional insulin production in response to glucose levels. Furthermore, patients spent 13% more time in target glucose range, with some able to reduce the amount of their injected insulin.

Authors of the Cell Reports Medicine paper write about 17 subjects with type 1 diabetes who were also implanted with PEC-Direct. Results indicate positive C-peptide levels as early as six months post-implant in some patients. These data suggest that pancreatic endoderm cells can be differentiated into, and offer a potential scalable, renewable source of, insulin-producing, pancreatic islet cells.

These insulin-producing cells are developed through a directed differentiation process that enables pluripotent stem cells to progress along a defined pathway and become precursor (endoderm) pancreatic cells. Once implanted, these cells then have the potential to further differentiate to become mature, fully-functioning islet cells.  As healthcare starts to pivot to regenerative medicine, this technology could be the dawn of a bright future for those living with type 1 diabetes, their caregivers and families, and even the physicians treating them.

But as futuristic as this work may seem, these results have been a work in progress. “The story dates back to 2014, when we implanted our first product, PEC-Encap, into humans,” says Howard L. Foyt, MD, PhD, chief medical officer at ViaCyte and corresponding author of the two papers.  “And at that time we had great data in pre-clinical models, and we thought we’d be off to the races and running. Unfortunately, clinical research is not a straight line from point A to point B. And we’ve faced down unexpected challenges, so to speak, so it’s taken longer than we anticipated.

“But the bottom line is that we’ve learned a lot along the way,” he continues. “And we’ve applied the lessons learned from one development program to our next program. And it really has facilitated our progress along the way.”

Closer than Ever to a Cure?

Foyt tells Endocrine News that the Cell Reports Medicine paper reports on work from three years ago, one of the team’s earliest cohorts. He says that the importance of the paper is that it provides the first proof of concept that it is possible to use a stem cell-derived therapy to produce insulin in patients with type 1 diabetes.

“The scientists working on stem cell-derived islets for the therapy of type 1 diabetes have made tremendous progress and deserve our congratulations. As one looks to the future, we await further advances in ongoing research pursuing strategies to avoid immune rejection (cell engineering, encapsulation, immunosuppression) while maintaining healthy oxygenated highly functioning islets.”

Daniel J. Drucker, PhD, professor of medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada

The research has progressed since then. At the American Diabetes Association meeting last year, Foyt and his team reported on one patient who was able to achieve a C-peptide level of 0.8 ng/mL, sufficient to have a significant glycemic impact. The patient’s hemoglobin A1C went from a baseline of 7.4% to 6.9% at 52 weeks.

Foyt says this patient had not achieved an A1C below 7.0% in the five years prior to entering the study. “The patient is now up to around a year and a half (of being treated with PEC-Direct) and the A1Cs are sustained, remaining below 7.0,” he says. “At the same time, exogenous insulin dose has decreased by as much as over 70% from its optimized level.”

The last parameter that’s important to note for these patients is time in range. All the participants enrolled in these trials have to be on continuous glucose monitors. This same patient went from a baseline time in range of 54% to 89%. “Some of the recent times in range have been greater than 90%,” Foyt says. “And that’s very impressive.”

Impressive indeed. After ViaCyte’s presentation at the ADA meeting, the non-profit T1D Exchange wrote that the company is “closer than ever to find a functional cure for diabetes.” That’s certainly a possibility, but there’s still work to be done.

Currently, patients implanted with PEC-Direct have to be on chronic immunosuppression. That product is directed at high-risk patients with type 1 diabetes who have either hypoglycemia unawareness or extreme glycemic lability. But ViaCyte has recently entered into a collaboration with CRISPR Therapeutics leveraging their technology to develop a gene-edited version of the product to be immune evasive, which the researchers refer to as VCTX210, and they are recruiting participants to help put that to the test.

“With VCTX210, if we are successful in eliminating the requirement for immunosuppression, it can not only be used to treat type 1 diabetes patients, but also potentially be an adjunct therapy for insulin-requiring type 2 patients,” Foyt says. “Once we progress beyond these earlier stages of development for the diabetes products, it may be possible to apply the same regenerative medicine technology to other indications that would be amenable to cellular replacement therapy, such as treatments for thyroid or parathyroid glands.”

Patient Patients

If that functional cure for type 1 diabetes really is within reach, then it may be a matter of serendipity that the investigator who did the first islet cell transplant in 2001 was James Shapiro, MD, PhD, Canada Research Chair and Director of the Islet Transplant Program at the University of Alberta, Canada. (Shapiro is also the lead author of the Cell Reports Medicine paper.) After all, it’s a source of pride for Canada that insulin changed the world, and now that pride can swell if they can claim a functional cure for diabetes as well.

The potential therapeutic benefits of PEC-Direct take a bit more time to be manifested compared to an islet cell transplant. Investigators report that the patients think the product is having an immediate, positive therapeutic effect, but it takes time for the precursor pancreatic cells to differentiate in vivo to become mature islet cells. Patients must have patience when it comes to decreasing their insulin dose. “At the same time, since the cells are contained within a device, the device has to become vascularized so that you can have this exchange of information between the systemic circulation and the graft cells contained in the lumen of the device,” Foyt explains. “That vascularization takes time as well. Consequently, there’s a lag phase between the implantation and when you start to see elevated levels of C-peptide.”

Still, the researchers have found that whereas it once took six to nine months to see the appearance of C-peptide, they’re now finding it only takes three to four months.

Beyond Diabetes and Endocrinology

There also might be pushback from physicians who still shy away from anything with the phrase “stem cell” attached to it. There are some who bring up ethical issues surrounding stem cell technology, but Foyt says all of this work has been possible because of the donation of a single embryo from a couple who had been undergoing in vitro fertilization. When the couple completed their family, they elected, under informed consent, to donate this embryo to science in 2004.

“And from that single embryo, we generated cell banks that have allowed us to do all of the research to date,” Foyt says. “Because of the vast potential of stem cells to regenerate, these cell banks have the potential to generate billions of cells, to the point that we could potentially treat every patient with diabetes on the planet.”

“And as for the people who believe otherwise, we respect their beliefs,” Foyt continues, “but we also feel that the power and the potential for the millions of patients who could benefit from this type of therapy far outweigh any objections.”

“Stem cell technology is remarkable in that you can generate literally billions of cells for these different treatment modalities. And we think we are in the process of demonstrating the potential of this type of cellular replacement therapy on type 1 diabetes. But that the potential goes far beyond diabetes and even endocrinology for that matter.”

Howard L. Foyt, MD, chief medical officer, ViaCyte, San Diego, Calif.

Moreover, these findings could have vast implications for healthcare. “The scientists working on stem cell-derived islets for the therapy of type 1 diabetes have made tremendous progress and deserve our congratulations,” says Daniel J. Drucker, at the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto and editor-in-chief of Endocrine Reviews. “As one looks to the future, we await further advances in ongoing research pursuing strategies to avoid immune rejection (cell engineering, encapsulation, immunosuppression) while maintaining healthy oxygenated, highly functioning islets.”

Adds Foyt, “Stem cell technology is remarkable in that you can generate literally billions of cells for these different treatment modalities,” Foyt says. “And we think we are in the process of demonstrating the potential of this type of cellular replacement therapy with type 1 diabetes. But the potential goes far beyond diabetes and even endocrinology for that matter.”

— Bagley is the senior editor of Endocrine News. He wrote about the Endocrine Society’s Policy Perspective on eradicating racism in endocrinology in the March issue.