Insulin release from engrafted cells has been demonstrated in individuals with type 1 diabetes, according to preliminary results from a multinational clinical trial. The implants, which were made of pancreatic endoderm cells generated from human pluripotent stem cells (PSCs), were examined in 26 patients for safety, acceptability, and efficacy.
Despite the fact that the insulin secreted by the implants had no therapeutic impact in the patients, the findings are the first evidence of meal-regulated insulin secretion by differentiated stem cells in humans. The findings were published in the journals Cell Stem Cell and Cell Reports Medicine on 2nd December 2021.
“A landmark has been set. The possibility of an unlimited supply of insulin-producing cells gives hope to people living with type 1 diabetes,” says Eelco de Koning of Leiden University Medical Center, a co-author of an accompanying commentary 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.”
Type 1 diabetes is still a life-altering and often life-threatening diagnosis nearly 100 years after the discovery of the hormone insulin. The condition is characterized by the loss of insulin-producing?-cells in the pancreas’ Islets of Langerhans, resulting in excessive blood glucose levels.
Insulin treatment reduces glucose levels but does not bring them back to normal. Furthermore, current insulin delivery systems can be uncomfortable to wear for long periods of time, have a tendency to malfunction, and frequently result in long-term consequences.
While islet replacement treatment has the potential to heal diabetes by restoring insulin secretion in the body, it has not been extensively embraced due to a scarcity of donor organs. These difficulties highlight the necessity for a large alternative supply of insulin-producing cells.
The clinical road to wide implementation of stem cell-derived islet replacement therapy for type 1 diabetes is likely to be long and winding. Until that time, donor pancreas and islet transplantation will remain important therapeutic options for a small group of patients. But an era of clinical application of innovative stem-cell-based islet replacement therapy for the treatment of diabetes has finally begun.
Eelco de Koning
Human pluripotent stem cells (hPSCs) have made tremendous progress toward becoming a clinically feasible option for the bulk generation of insulin-producing cells. Novocell (formerly ViaCyte) scientists published a multi-stage methodology in 2006 that directed the differentiation of human embryonic stem cells into immature pancreatic endoderm cells.
The embryonic development of the pancreas inspired this step-by-step methodology for modifying critical signaling networks. When these pancreatic endoderm cells were implanted in animal models, follow-up investigations revealed that they were able to grow further and become fully functional. Clinical experiments with these pancreatic endoderm cells have begun as a result of these findings.
Two groups have now published a phase I/II clinical trial in which pancreatic endoderm cells were implanted under the skin in patients with type 1 diabetes in non-immunoprotective (“open”) macroencapsulation devices that allowed for direct vascularization of the cells.
The use of off-the-shelf cells in this stem cell-based islet replacement method necessitated the use of immunosuppressive drugs, which protect against graft rejection but can have serious adverse effects like cancer and infections. The subjects were given an immunosuppressive therapy similar to that used in donor islet transplant surgery.
Timothy Kieffer of the University of British Columbia and his colleagues published convincing evidence of functioning insulin-secreting cells following implantation in the journal Cell Stem Cell. Within 26 weeks of implantation, PEC-01s, ViaCyte’s drug candidate pancreatic endoderm cells, survived and developed into glucose-responsive, insulin-secreting cells.
Patients reported a 20% reduction in insulin requirements and spent 13% more time in the target blood glucose range after a year of follow-up. The implants were generally well tolerated, with no serious graft-related complications.
“For the first time, we provide evidence that stem cell-derived PEC-01s can mature into glucose-responsive, insulin-producing mature?-cells in vivo in patients with type 1 diabetes,” Kieffer says. “These early findings support future investment and investigation into optimizing cell therapies for diabetes.”
Two individuals, however, developed substantial side effects as a result of the immunosuppressive treatment. Furthermore, because there was no control group and the therapies were not blinded, causal implications could not be drawn, and the outcomes were very diverse among the limited number of individuals.
Furthermore, more research is needed to discover the appropriate dose of pancreatic endoderm cells to achieve clinically relevant advantages for patients. Howard Foyt of ViaCyte and his colleagues reported engraftment and insulin expression in 63 percent of devices explanted from trial patients at 3 to 12 months after implantation in Cell Reports Medicine.
From the time of implant, functioning, insulin-secreting cells gradually accumulated over a period of roughly 6-9 months. The majority of adverse events were linked to surgical implant or explant operations, as well as immunosuppressive side effects.
Despite systemic immune suppression, several surgical implantation sites, and the presence of foreign materials, the risk of local infection was extremely low, indicating that this method is well tolerated in people who have a poor healing response. Currently, researchers are looking on ways to improve transplant vascularization and survival.
“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,” Foyt says.
Both studies found that the grafts were vascularized and that the device’s cells could live for up to 59 weeks after being implanted. Furthermore, no teratomas (tumors of the uterus) developed.
However, as compared to mature pancreatic islets, the ratio of distinct endocrine cell types was unusual, and the total percentage of insulin-positive cells in the device was low.
In terms of safety, the majority of serious adverse events were linked to the usage of immunosuppressive medicines, stressing the need for these treatments to be taken for the rest of one’s life as a major barrier to wider use of cell replacement therapy.
“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,” says Françoise Carlotti of Leiden University Medical Center, a co-author of the related commentary.
Many questions, according to de Koning and Carlotti, remain unanswered. Researchers must, for example, establish the stage of differentiation at which the cells are most suitable for transplantation and the ideal transplantation site.
It’s also unclear whether the cells’ efficiency and safety can be maintained over time, or whether immunosuppressive medication can be eliminated entirely.
“The clinical road to wide implementation of stem cell-derived islet replacement therapy for type 1 diabetes is likely to be long and winding. Until that time, donor pancreas and islet transplantation will remain important therapeutic options for a small group of patients,” de Koning says. “But an era of clinical application of innovative stem-cell based islet replacement therapy for the treatment of diabetes has finally begun.”
