Insulin Expression and Glucose-Responsive Circulating C-Peptide in Type 1 Diabetes Patients Implanted Subcutaneously with Pluripotent Stem Cell-Derived Pancreatic Endoderm Cells in a Macro-Device

Shapiro, AM James; Thompson, David M.; Donner, Thomas; Bellin, Melena D.; Hsueh, Willa A.; Pettus, Jeremy; Wilensky, Jon; Daniels, Mark; Wang, Richard M.; Kroon, Evert; Brandon, Eugene P.; D’Amour, Kevin A.; Foyt, Howard L.

doi:10.2139/ssrn.3501034

Cited by 14 publications

(11 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Explanted grafts contained cells with a mature b cell phenotype that were immunoreactive for insulin, islet amyloid polypeptide, and MAFA. These data, and associated findings (Shapiro et al, 2021), are the first reported evidence of meal-regulated insulin secretion by differentiated stem cells in patients.*No ACR sample was collected, but patients had negative protein on a urine dipstick test. BMI, Body mass index; ACR, albumin-creatinine ratio; MDI, multiple daily injections.…”

mentioning

confidence: 65%

Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes

et al. 2021

View full text Add to dashboard Cite

An open-label, first-in-human phase 1/2 study is being conducted to evaluate the safety and efficacy of pancreatic endoderm cells (PECs) implanted in non-immunoprotective macroencapsulation devices for the treatment of type 1 diabetes. We report an analysis on 1 year of data from the first cohort of 15 patients from a single trial site that received subcutaneous implantation of cell products combined with an immunosuppressive regimen. Implants were well tolerated with no teratoma formation or severe graft-related adverse events. After implantation, patients had increased fasting C-peptide levels and increased glucose-responsive C-peptide levels and developed mixed meal-stimulated C-peptide secretion. There were immunosuppression-related transient increases in circulating regulatory T cells, PD1 high T cells, and IL17A + CD4 + T cells. Explanted grafts contained cells with a mature b cell phenotype that were immunoreactive for insulin, islet amyloid polypeptide, and MAFA. These data, and associated findings (Shapiro et al., 2021), are the first reported evidence of meal-regulated insulin secretion by differentiated stem cells in patients.*No ACR sample was collected, but patients had negative protein on a urine dipstick test. BMI, Body mass index; ACR, albumin-creatinine ratio; MDI, multiple daily injections. ll Clinical and Translational Report

show abstract

mentioning

confidence: 65%

Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The purpose of this trial is also to test whether VC-02 is an effective treatment. PEC-01 cells were able to engraft, survive, and produce measurable C-peptide levels (95). Preliminary results from a small subset of patients (six out of 18) showed substantial engraftment of sentinel devices containing insulin positive cells (9 months after transplantation), and production of C-peptide in all patients up to 12-months (with some patients already reaching 15, 18, or 21 months).…”

Section: Pluripotent Stem Cell-based Clinical Trialsmentioning

confidence: 90%

Stem Cell-Based Clinical Trials for Diabetes Mellitus

Klerk

Hebrok

2021

Front. Endocrinol.

View full text Add to dashboard Cite

Since its introduction more than twenty years ago, intraportal allogeneic cadaveric islet transplantation has been shown to be a promising therapy for patients with Type I Diabetes (T1D). Despite its positive outcome, the impact of islet transplantation has been limited due to a number of confounding issues, including the limited availability of cadaveric islets, the typically lifelong dependence of immunosuppressive drugs, and the lack of coverage of transplant costs by health insurance companies in some countries. Despite improvements in the immunosuppressive regimen, the number of required islets remains high, with two or more donors per patient often needed. Insulin independence is typically achieved upon islet transplantation, but on average just 25% of patients do not require exogenous insulin injections five years after. For these reasons, implementation of islet transplantation has been restricted almost exclusively to patients with brittle T1D who cannot avoid hypoglycemic events despite optimized insulin therapy. To improve C-peptide levels in patients with both T1 and T2 Diabetes, numerous clinical trials have explored the efficacy of mesenchymal stem cells (MSCs), both as supporting cells to protect existing β cells, and as source for newly generated β cells. Transplantation of MSCs is found to be effective for T2D patients, but its efficacy in T1D is controversial, as the ability of MSCs to differentiate into functional β cells in vitro is poor, and transdifferentiation in vivo does not seem to occur. Instead, to address limitations related to supply, human embryonic stem cell (hESC)-derived β cells are being explored as surrogates for cadaveric islets. Transplantation of allogeneic hESC-derived insulin-producing organoids has recently entered Phase I and Phase II clinical trials. Stem cell replacement therapies overcome the barrier of finite availability, but they still face immune rejection. Immune protective strategies, including coupling hESC-derived insulin-producing organoids with macroencapsulation devices and microencapsulation technologies, are being tested to balance the necessity of immune protection with the need for vascularization. Here, we compare the diverse human stem cell approaches and outcomes of recently completed and ongoing clinical trials, and discuss innovative strategies developed to overcome the most significant challenges remaining for transplanting stem cell-derived β cells.

show abstract

“…Preliminary results from the first clinical trial with pancreatic endodermal cells in immunoprotective macroencapsulation devices highlighted the difficulties for this approach with minimal tissue engraftment and differentiation into insulin-producing cells 60 . In a subsequent trial, modification of the device allowing direct vascularization of the engrafted cells resulted in better differentiation; however, the level of insulin production and the number of insulin-positive cells remained low 61 . Grafts in mice from further differentiated hormone-expressing populations can also form cysts, which are structures consisting of cells with duct properties that might continue to grow over time, as long as progenitor cells are present in the final mix 52,62 .…”

Section: Key Pointsmentioning

confidence: 98%

Emerging routes to the generation of functional β-cells for diabetes mellitus cell therapy

2020

View full text Add to dashboard Cite

Diabetes mellitus, which affects more than 463 million people globally, is caused by the autoimmune ablation or functional loss of insulin-producing β-cells, and prevalence is projected to continue rising over the next decades. Generating β-cells to mitigate the aberrant glucose homeostasis manifested in the disease has remained elusive. Substantial advances have been made in producing mature β-cells from human pluripotent stem cells that respond appropriately to dynamic changes in glucose concentrations in vitro and rapidly function in vivo following transplantation in mice. Other potential avenues to produce functional β-cells include: transdifferentiation of closely related cell types (for example, other pancreatic islet cells such as α-cells, or other cells derived from endoderm); the engineering of nonβ-cells that are capable of modulating blood sugar; and the construction of synthetic 'cells' or particles mimicking functional aspects of β-cells. This Review focuses on the current status of generating β-cells via these diverse routes, highlighting the unique advantages and challenges of each approach. Given the remarkable progress in this field, scalable bioengineering processes are also discussed for the realization of the therapeutic potential of derived β-cells.

show abstract

Insulin Expression and Glucose-Responsive Circulating C-Peptide in Type 1 Diabetes Patients Implanted Subcutaneously with Pluripotent Stem Cell-Derived Pancreatic Endoderm Cells in a Macro-Device

Cited by 14 publications

References 0 publications

Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes

Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes

Stem Cell-Based Clinical Trials for Diabetes Mellitus

Emerging routes to the generation of functional β-cells for diabetes mellitus cell therapy

Contact Info

Product

Resources

About