Advancements in transplantation therapy for diabetes: Pancreas, islet and stem cell

Abstract

Pancreas transplantation and islet transplantation are now established in the treatment of IDDM. Several trials of stem cell‐derived cell transplantation therapy are underway and may offer an alternative to the limited supply of donor islets in the near future. This article summarizes recent developments in transplantation therapy for diabetes as well as research on the use of stem cells for complications of diabetes.

In the 100‐year history of exogenous insulin therapy for patients with insulin‐dependent diabetes mellitus (IDDM), pancreas transplantation and islet transplantation have gained wide acceptance over recent decades. In addition, research and development of human stem cell‐derived cell transplantation have accelerated in recent years ¹ . Several preclinical approaches using somatic stem cells for the complications of diabetes also have been explored. This article summarizes recent developments in transplantation therapy for diabetes, including ongoing trials, as well as research on the use of stem cells for complications of diabetes.

Pancreas Transplantation to Islet Transplantation

Pancreas transplantation (PTx) was developed in the 1960s as a definitive treatment for IDDM patients. PTx is classified into three categories: (i) simultaneous pancreas‐kidney transplantation; (ii) pancreas after kidney transplantation; and (iii) pancreas transplantation alone. The outcome of PTx improved as the number of transplantations drastically increased in the 1990s. Among the three categories, simultaneous pancreas‐kidney transplantation showed the highest graft survival rate, reaching 85.5% at 1 year after transplantation in the 2006–2010 period. Simultaneous pancreas‐kidney transplantation accounted for 75% of PTx reported in the International Pancreas Transplantation Registry in 2010 ² . However, PTx requires relatively invasive abdominal surgery with vascular anastomosis and enteric or bladder drainage, and the patient survival rate remained 95–96% at 3 years in the 2010–2014 period, in which the main causes of mortality were cardiovascular or cerebrovascular events and infection ³ .

To minimize the complications, islet transplantation (ITx), which requires only percutaneous intraportal infusion of isolated donor islets with a small incision, was developed in the 1970s. ITx was regarded as a “low risk/low return” method in its early days, but the University of Alberta group turned the tide when they published auspicious results in 2000 using a glucocorticoid‐free immunosuppressive regimen called the Edmonton Protocol. They showed that seven of seven consecutive patients attained insulin‐free status at a median 11.9‐month follow up, having received 9,400–14,000 islet equivalent/kg of the recipient’s bodyweight in total from several donors ⁴ . Although most of the Edmonton Protocol‐based ITx cases required supplemental exogenous insulin injection over the 10‐year follow‐up period, the protocol is thought to be safe, with acceptable side‐effects and no mortality compared with multiple daily injections/continuous subcutaneous insulin infusion therapy ⁵ , ⁶ . Furthermore, in 2005, a University of Minnesota group showed that five of eight patients remained insulin‐independent for >1 year with 5,900–8,700 islet equivalent/kg from only a single cadaver donor by using a novel induction regimen using anti‐thymocyte globulin and etanercept ⁷ ; they then carried out a following CIT‐07 multicenter trial according to this regimen. The primary end‐point of CIT‐07 was achievement of glycated hemoglobin <7.0% at 1 year and freedom from severe hypoglycemic events from day 28 to 1 year after the first transplantation. The results of CIT‐07 reported in 2016 showed that 87.5% of 48 patients achieved the primary end‐point, and that the insulin independence rate was 52.1% at 1 year with no mortality ⁸ . ITx with this regimen also improved glycemic variability with appropriate glucagon secretion during hypoglycemia ⁹ .

Stem Cell‐Derived Cell Transplantation in Humans

The current transplantation strategy for diabetes receiving the most attention is stem cell‐derived cells that mimic pancreatic islet cells in vivo. Candidate cell sources are human embryonic stem cells (hESCs), human induced pluripotent stem cells (hiPSCs) and transdifferentiated cells from pancreatic exocrine cells ¹⁰ . Among these, hESCs are presently at the forefront. Several clinical trials led by ViaCyte Inc. using subcutaneous transplantation of hESC‐derived cells encapsulated in a small device, VC‐01 or VC‐02, have already been recently launched in the USA and Canada. VC‐01 was developed to use without immunosuppressant. It is a complex of pancreatic endoderm cells differentiated from hESCs in vitro in an immunoisolating encapsulation device that does not permit inward vascularization. The STEP ONE (A Safety, Tolerability and Efficacy Study of VC‐01™ Combination Product in Subjects with Type 1 Diabetes Mellitus, NCT02239354) trial was carried out with 19 participants as an open‐label phase 1/2 trial. No potential side‐effects were noted. However, difficulties remain regarding long‐term engraftment, as in most cases surviving cells were sparse after 12 weeks, mainly as a results of hypoxia caused by a siege of foreign giant body cells ¹¹ , ¹² . Thus, to improve graft viability, there might be a shift of interest to VC‐02. VC‐02 comprises pancreatic endoderm cells with an encapsulation device that allows vascular ingrowth, which is expected to show higher viability, but requires immunosuppressants. A phase 1/2 study (A Safety, Tolerability, and Efficacy Study of VC‐02™ Combination Product in Subjects with Type 1 Diabetes Mellitus and Hypoglycemia Unawareness, NCT03163511) is now underway. In contrast, research on hiPSC‐derived cell transplantation is being led by Takeda Pharmaceutical Company Ltd. and the Center for iPS Cell Research and Application, Kyoto University (T‐CiRA Joint Program) in Japan by using hiPSC‐derived islet‐like cells called iPIC. Although still on the way to clinical application, iPIC has shown promising results in transplantation to immunodeficient mice ¹³ . In addition, disease‐modeling hiPSCs, including those for fulminant type 1 diabetes ¹⁴ and maturity onset diabetes of the young ¹⁵ , can offer clues to potential therapeutic drug targets.

Approaches to Complications of Diabetes

Another approach of stem cell research is to complications of diabetes. Several preclinical studies of neuropathy show encouraging results. Dental pulp stem cells produce angiogenic, neurotrophic and immunomodulatory factors ¹⁶ , and injection of conditioned media after culturing rat dental pulp stem cells into the hindlimb of diabetic rats improves sciatic motor/sensory nerve conduction velocity and sciatic nerve blood flow ¹⁷ . Similar methods using dental pulp stem cells from human exfoliated deciduous teeth facilitate neurite outgrowth of dorsal root ganglion neurons of mice in vitro, and sensory nerve conduction velocity after injection of the conditioned media into the soleus of mice ¹⁸ . Regarding nephropathy, subrenal capsule transplantation of adipose‐derived mesenchymal stem cells from rats reduces albuminuria and urinary tumor necrosis factor‐alpha and interleukin‐6 levels of diabetic rats, which is presumed to be the result of renoprotective paracrine factors ¹⁹ .

Summary

Advances in transplantation therapies for IDDM patients are shown in chronological order in Figure 1. Pancreas transplantation and islet transplantation are now established in the treatment of IDDM. Several trials of stem cell‐derived cell transplantation therapy are underway, and might offer an alternative to the limited supply of donor islets in the near future. Regarding the complications of diabetes, several approaches using tissue stem cells are being pursued.

Figure 1.

Advancements in transplantation therapy for diabetes.

Exogenous insulin therapy is the life‐saving, gold standard therapy for patients with insulin‐dependent diabetes mellitus from its early days to the present, but it has a risk of severe hypoglycemia, which is due to insufficient mimicking of the endogenous insulin secretion pattern. Pancreas transplantation was developed in the 1960s to overcome this severe hypoglycemia risk by means of the endogenous glucose‐stimulated insulin secretion (GSIS) of a graft, and the method attained a high insulin‐free rate. To minimize the complications of pancreas transplantation, which requires laparotomy, islet transplantation, which requires only percutaneous intraportal infusion of isolated donor islets using a small incision, was developed in the 1970s. Recently, to overcome donor shortage and to accomplish a stable graft supply, research on stem cell‐derived cells that mimic pancreatic islet cells in vivo has been accelerating and shifted to the clinical phase in the 2010s.

Disclosure

NI received clinical commissioned/joint research grants from Daiichi Sankyo, Terumo, and Drawbridge Inc.; speaker honoraria from Kowa, MSD, Astellas Pharma, Novo Nordisk Pharma, Ono Pharmaceutical, Nippon Boehringer Ingelheim, Takeda, Sumitomo Dainippon Pharma and Mitsubishi Tanabe Pharma; and scholarship grants from Kissei Pharmaceutical, Sanofi, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Takeda, Japan Tobacco, Kyowa Kirin, Sumitomo Dainippon Pharma, Astellas Pharma, MSD, Eli Lilly Japan, Ono Pharmaceutical, Sanwa Kagaku Kenkyusho, Nippon Boehringer Ingelheim, Novo Nordisk Pharma, Novartis Pharma, Teijin Pharma and Life Scan Japan. The other authors declare no conflict of interest.

J Diabetes Investig 2021; 12: 143–145