For the first time, scientists have derived insulin-secreting pancreatic endoderm cells from human pluripotent stem cells (PSCs), grafted these cells into 26 patients with type 1 diabetes, and demonstrated insulin secretion. The ongoing multicenter clinical trial aims to test the safety, tolerability, and efficacy of the implants. These results constitute the first evidence of meal-regulated insulin secretion from implanted cells for over a year, although the insulin secreted by the implants did not have clinically relevant effects in the patients.

“A landmark has been set. The possibility of an unlimited supply of insulin-producing cells gives hope to people living with type 1 diabetes,” said Eelco de Koning, PhD, of Leiden University Medical Center, and a co-author of a commentary on the study published in Cell Stem Cell. “Despite the absence of relevant clinical effects, this study will remain an important milestone for the field of human PSC-derived cell replacement therapies as it is one of the first to report cell survival and functionality one year after transplantation.”

The interim results of the trial appear in two articles published on December 2:  “Insulin expression and C-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device,” in the journal Cell Reports Medicine, and “Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes,” in the journal Cell Stem Cell.

Timothy Kieffer, PhD, professor at the University of British Columbia and senior author on the Cell Stem Cell paper said, “This work provides proof-of-concept for a stem cell derived insulin replacement in patients with type 1 diabetes. We show that lab-made pancreatic progenitors can survive and mature into cells capable of meal-regulated insulin production when implanted subcutaneously within macro-encapsulation devices. This is significant because it supports the idea that with further optimization, this approach can be used to free patients from the burden of daily insulin injections.”

Insulin was discovered in 1921 and yet 100 years later type 1 diabetes, a disease marked by the destruction of insulin-producing beta-cells in the pancreatic Islets of Langerhans remains a life-altering if not life-threatening diagnosis. Insulin allows cells in the body to take up glucose from digested food. In the absence of insulin, cells cannot take up glucose and its levels rise in blood even as the cells remain starved for it.

Daily injections of insulin, the current treatment option for patients with type 1 diabetes, temporarily decreases glucose levels in the blood but do not normalize them. Modern insulin delivery devices are a burden to wear. They can malfunction at time and may also lead to long-term complications.

Grafting healthy insulin-secreting cells in patients offer a potential cure for the disease. However, the scarcity of donor organs poses a substantial obstacle to islet replacement therapy. Creating an abundant alternate supply of insulin-producing cells is therefore of utmost therapeutic significance. In the past decades progress has been made in using PSCs—cells that can be differentiated into any specialized cell type under the right conditions—to mass produce insulin-producing cells.

In 2006, based on key signaling components that direct the embryonic development of the pancreas, scientists at Novocell (now ViaCyte) developed multi-stage protocol to differentiate human embryonic stem cells into immature pancreatic endoderm cells that mature and become fully functional when implanted in animal models. A Phase I/II clinical trial has now attempted to therapeutically exploit these differentiated pancreatic endoderm cells.

In this trial the pancreatic endoderm cells were placed in non-immunoprotective (“open”) macroencapsulation devices and implanted under the skin in patients with type 1 diabetes. The open design allows blood vessels to grow toward the engrafted cells which is critical in transporting the secreted insulin into the bloodstream. Both reports showed that the grafts were vascularized and that cells in the device survive for up to 59 weeks after implantation.

Since the stem cells used as the source material were third-party off-the-shelf cells, the patients needed to be treated with immunosuppressive agents which protects against graft rejection but can cause major side effects, such as cancer and infections.

In the paper in Cell Stem Cell, Kieffer and his collaborators report PEC-01s—the pancreatic endoderm cells drug candidate produced by ViaCyte—survived and matured into glucose-responsive, insulin-secreting cells within 26 weeks after implantation. At the one-year follow-up, patients had 20% reduced insulin requirements, and spent 13% more time in the target blood glucose range.

“We provide evidence that stem cell-derived PEC-01s can mature into glucose-responsive, insulin-producing mature β-cells in vivo in patients with type 1 diabetes,” Kieffer said. “These early findings support future investment and investigation into optimizing cell therapies for diabetes.”

Although the implants were well tolerated overall with no severe graft-related adverse events, two patients experienced serious adverse reactions to the immunosuppression protocol. Other limitations of the trial were the small number of participants, the lack of a control group, and that the interventions were not blinded. Further studies will be needed to determine the dose of pancreatic endoderm cells necessary to achieve clinically relevant benefits.

In the article in Cell Reports Medicine, Howard Foyt, MD, PhD, of ViaCyte and his collaborators report insulin expression in 63% of the implanted devices between 3 to 12 months after implantation. The implants showed progressive accumulation of functional, insulin-secreting cells over approximately 6–9 months from the time of implant.

“The present study demonstrates definitively for the first time to our knowledge, in a small number of human subjects with type 1 diabetes, that PSC-derived pancreatic progenitor cells have the capacity to survive, engraft, differentiate, and mature into human islet-like cells when implanted subcutaneously,” said Foyt.

Adverse events were related to surgical implant or explant procedures or to immunosuppression. There was no formation of tumors in the grafts. The ratio of different endocrine cell types in the graft was not similar to that in mature pancreatic islets, and the total percentage of insulin-positive cells in the device was relatively low. The researchers are currently working on ways to increase graft vascularization and survival.

“An ideal and sunny possible future scenario would be the wide availability of a safe and efficacious stem cell-based islet replacement therapy without the need for these immunosuppressive agents or invasive, high-risk transplantation procedures,” said Françoise Carlotti, PhD, of Leiden University Medical Center, a co-author of the commentary on the trial.

“Our ultimate goal is to achieve full insulin independence for patients, without the need for chronic immunosuppression,” said Kieffer.

Future studies will need to determine the differentiation stage at which it is best to transplant the cells and the optimal location for transplantation. Long-term follow-ups will need to determine the effectiveness and safety of the grafted cells over time, and the possibility of eliminating the need for immunosuppressive therapy.

“At the American Diabetes Association annual conference this summer, ViaCyte reported dramatic reductions in insulin usage with vastly improved glucose control in a patient who received more devices (8, compared to the 2–4 we used in this study),” said Kieffer. Kieffer’s team also intends to to increase the numbers of insulin producing cells within the devices to improve glucose control in patients.

To eliminate the need for the immunosuppression, ViaCyte is collaborating with GORE to develop fully enclosed devices that will isolate the cells within from host immune cells. ViaCyte is also working with CRISPR Therapeutics to create genetically modified cells that are immune-evasive, as an alternative approach. Health Canada has approved testing these new cells in patients.

“Trials will begin soon in which the cells are implanted without any immune suppression.  It will be exciting to see these approaches develop,” said Kieffer.

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