Stem cell-based implants successfully secrete insulin in patients with type 1 diabetes


A high resolution model of six insulin molecules assembled into a hexamer. Credit: Isaac Yonemoto / Wikipedia

Interim results from multicenter clinical trials show insulin secretion from transplanted cells in patients with type 1 diabetes. Twenty-six patients were tested for the safety, tolerability, and efficacy of implants consisting of pancreatic endoderm cells derived from human pluripotent stem cells (PSCs). Although insulin secreted by the implant had no clinical effect on the patient, the data are the first reported evidence of dietary regulatory insulin secretion by differentiated stem cells in human patients.Results will be displayed in the journal on December 2nd Cell stem cell When Cell Reports Medicine..

“A breakthrough event has been set. Possibility of unlimited supply of insulin production cell It gives hope to people with type 1 diabetes, “said Eelco de Koning of the Leiden University Medical Center. Cell stem cell.. “Despite the lack of associated clinical efficacy, this study is one of the first to be reported and will continue to be an important milestone in the field of human PSC-derived cell replacement therapy. Cell survival Function one year after transplantation. “

Approximately 100 years after the discovery of the hormone insulin, type 1 diabetes remains a life-changing and sometimes life-threatening diagnosis. The disease is characterized by the destruction of insulin-producing beta cells in the islets of Langerhans in the pancreas, resulting in high levels of blood glucose.

Insulin treatment lowers glucose levels, but does not completely normalize them. In addition, modern insulin delivery systems are cumbersome to wear for long periods of time, sometimes dysfunctional, and can often cause long-term complications.Although islet replacement therapy can provide a cure as it recovers Insulin secretion This procedure has not been widely adopted due to the lack of donor organs in the body. These challenges underscore the need for an abundant alternative supply of insulin-producing cells.

The use of human PSC has made great strides towards becoming a viable clinical option for the mass production of insulin-producing cells. In 2006, scientists at Novocell (now ViaCyte) reported a multi-step protocol that directs the differentiation of human embryos. Stem cells For immature pancreatic endoderm cells. This step-by-step protocol for manipulating important signaling pathways was based on the development of pancreatic embryos. Follow-up studies have shown that these pancreatic endoderm cells can become more mature and fully functional when transplanted into animal models. Based on these results Clinical trials We started using these pancreatic endoderm cells.

Currently, two groups have placed pancreatic endoderm cells in a non-immune-protected (“open”) macroencapsulation device, allowing direct angiogenesis of the cells and transplanting them under the skin of type 1 patients. We are reporting on Phase II clinical trials. Diabetes mellitus. The use of third-party off-the-shelf cells in this stem cell-based islet replacement strategy required immunosuppressive agents that protect against graft rejection but can cause major side effects such as cancer and infections. .. Participants received an immunosuppressive treatment regimen commonly used in donor islet transplant procedures.

of Cell stem cellTimothy Keefer of the University of British Columbia and his collaborators provided compelling evidence of functional insulin-secreting cells after transplantation. PEC-01s (a drug candidate pancreatic endoderm cell produced by ViaCyte) survived within 26 weeks after transplantation and matured into glucose-responsive insulin-secreting cells. With up to a year of follow-up, patients reduced their insulin requirements by 20% and spent 13% more time within their target blood glucose levels. Overall, the implant was well tolerated and there were no serious adverse events associated with the graft.

“For the first time, we provide evidence that stem cell-derived PEC-01 can mature into glucose-responsive insulin-producing mature β-cells. In vivo In patients with type 1 diabetes, these early discoveries support future investments and research to optimize cell therapy for diabetes.

However, two patients experienced serious adverse events associated with immunosuppressive protocols. In addition, there were no controls, interventions were not blinded, causal conclusions were limited, and results varied significantly among a small number of participants. In addition, further research needs to determine the dose of pancreatic endoderm cells needed to achieve clinically relevant benefits to the patient.

of Cell Reports MedicineVia Cyte’s Howard Foyt and his collaborators reported engraftment and insulin expression in 63% of devices explanted from the study during the 3-12 month post-transplant period. Progressive accumulation of functional insulin-secreting cells occurred over a period of approximately 6-9 months from the time of transplantation.

Most of the reported adverse events were associated with surgical implant or explant procedures, or immunosuppressive side effects. Despite strong systemic immunosuppression, multiple surgical transplant sites, and the presence of foreign bodies, the risk of local infection is very low, and this approach is well tolerated in subjects at risk of poor healing response. It suggests that it will be done. Researchers are currently working on ways to promote angiogenesis and survival in grafts.

“This study, for the first time to our knowledge, demonstrates that PSC-derived pancreatic progenitor cells have the ability to survive, engraft, differentiate, and mature like human islets in a small number of human subjects with type 1 diabetes. It shows cells when transplanted subcutaneously, “says Foit.

Both reports showed that the graft was angiogenic and that the cells in the device could survive up to 59 weeks after transplantation. Graft analysis revealed the presence of major islet cell types, including β-cells. In addition, there was no formation of a tumor called a teratoma. However, the proportion of different endocrine cell types was atypical compared to mature islets, and the total percentage of insulin-positive cells in the device was relatively low.

In terms of safety, the most serious adverse events have been associated with the use of immunosuppressive agents, highlighting the lifelong use of these agents as a major hurdle for the wider implementation of these types of cell replacement therapies. .. “The ideal and sunny future scenario is the widespread availability of safe and effective stem cell-based pancreatic islet replacement therapy without the need for these immunosuppressive agents or invasive and high-risk transplant procedures.” Francoise Carlotti of the Leiden University Medical Center said, co-author of the relevant commentary.

According to de Koning and Carlotti, many questions need to be answered. For example, researchers need to determine the optimal differentiation stage for a cell to be transplanted and the optimal transplant site. It is also unclear whether cells can be maintained for long-term efficacy and safety, and whether the need for immunosuppressive therapy can be ruled out.

“The clinical path to widespread implementation of stem cell-derived islet replacement therapy for type 1 diabetes is likely to be long and winding. Until then, donor pancreas and islet transplantation remain important treatment options for a small group of patients. Probably, “de Corning says. “But the era of clinical application of innovative stem cell-based islet replacement therapy for the treatment of diabetes has finally begun.”

Beta cells from stem cells: potential cell replacement therapy

For more information:
Timothy J Kieffer, a transplanted pluripotent stem cell-derived pancreatic endoblast, secretes glucose-responsive C-peptide in patients with type 1 diabetes. Cell stem cell (2021). DOI: 10.1016 / j.stem.2021.10.003..… 1934-5909 (21) 00415-X

Howard Voith, Insulin Expression and C-Peptide in Type 1 Diabetes Patients Transplanted Stem Cell-Derived Pancreatic Germ Cell Cells in Encapsulation Device, Cell Reports Medicine (2021). DOI: 10.1016 / j.xcrm.2021.100466..… 2666-3791 (21) 00338-4

Quote: Stem cell-based implants were obtained from 2, 2021 for type 1 diabetes (December 2021). 2 days) normally secretes the patient’s insulin secrete.html

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