Stem Cell-Based Clinical Trials for Diabetes Mellitus

Abstract

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.

Hematopoiesis during Ontogenesis, Adult Life, and Aging

“…Significant numbers of other clinical trials are dealing with the use of MSCs' immunomodulatory properties as standalone therapy for various diseases and conditions associated with overactivated immune systems. MSCs were tested for treatment of rheumatoid arthritis and osteoarthritis [225], multiple sclerosis [226], inflammatory bowel disease [227], systemic lupus erythematosus [228], diabetes mellitus [229], among other pathologies. In most reported cases, good safety profiles and encouraging outcomes were reported.…”

Partners in Crime: Beta-Cells and Autoimmune Responses Complicit in Type 1 Diabetes Pathogenesis

“…While for years now, stem cellderived insulin-producing cells can be generated and studied in the lab, improvements in cell viability, identity, and reproducibility may be needed before they can be applied as a safe and affordable therapy (204). Beta-cell differentiation from multiple cell sources have been attempted, the most promising of which seem to be induced pluripotent stem cell (iPSC)-derived beta-cells (205). Clinical trials are in progress investigating the efficacy of treating T1D with one version of iPSC derived cells designed by Viacyte, Inc. and CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat) Therapeutics (NCT03163511).…”

Stem Cells as a Source of Pancreatic Cells for Production of 3D Bioprinted Bionic Pancreas in the Treatment of Type 1 Diabetes

“…Pre-clinical studies were also performed in the non-human primates by Vertex Farmaceuticals. Used islets-like organoids were able to decrease insulin intake by 60% [ 163 ].…”