Article by Leah Andrews & Roberta Lock
Implanting Stem Cell-derived Islet Cells for Type I Diabetes
Adam Ramzy et al., Timothy J.Kieffer Lab
Type 1 diabetes mellitus is a chronic disease in which the immune system attacks and destroys the pancreatic beta cells (the cells that make insulin) in the body. This results in an imbalance of blood glucose levels that can damage the vessels that supply nutrients to vital organs.
Negative feedback loop of blood sugar in the body
Recently, there have been significant scientific breakthroughs to transplant these cells to permanently increase insulin levels and remove the need for continuous administration of insulin therapy. In transplantation, healthy islets (clusters of beta cells) are removed from a deceased donor pancreas and injected into a patient’s vein to create and release insulin in the body. However, due to the number of patients diagnosed with diabetes and a limited number of donor matches there is a need for alternative methods to supply healthy beta cells. The paper addresses this issue by investigating human embryonic stem cell (hESC) derived beta cells as a potential alternative cell source for transplantation.
What did these researchers do?
In 2014, ViaCyte conducted a clinical trial evaluating ESC-derived pancreatic endoderm beta cell safety and efficacy. The results showed that patients had few complications, so they were safe. However, there was inconsistent cell survival due to the foreign body response and no insulin secretion, so efficacy was low. In this paper, ViaCyte and the Kieffer lab evaluate a secondary follow-up trial where the implanted cells are enclosed in an altered microencapsulated device and the patients are placed on immunosuppressants. One year after transplant, patients in this study reduced the need for regular exogenous insulin administration by 20% and 13% of patients spent more time in the target blood glucose range than in the initial preliminary trial.
Immunofluorescent stain of hormone-producing (Green) and duct-tissue (Red) cells in retrieved implants
Why is this important?
The results from this clinical trial can indicate whether the ESC-derived beta cells can be implanted into the human body and mature into insulin-secreting cells. The data could prove this is a successful method of regulating patient glucose levels, eliminating the need for the patient to regularly administer exogenous insulin manually. Additionally, ESCs are an effectively limitless cell source, so if ESC-derived beta cells are proven to be an effective way to regulate insulin levels, this will become a much more accessible treatment for patients.
How did the researchers do this?
A stepwise protocol was previously defined to differentiate ESCs into pancreatic endoderm beta cells. These cells were then placed in a microencapsulated device under the patient’s skin. This method of transplanting ESC-derived beta cells resulted in little insulin production but was successful in preventing hyperglycemia (high blood glucose) in diabetic mice. In this secondary study, the microencapsulation device was designed to have portals to enable direct vascular permeation into the device to minimize cell loss during transplantation as well as the addition of an immunosuppression regime to prevent patient immune response (which would attack the transplanted cells). Patients with type 1 diabetes were selected and screened for device implantation. The patients had the device implanted and attended scheduled visits assessing their glucose levels, daily insulin logs, and weight for over a year.
What comes next?
Although modest improvements in insulin and glucose regulation were seen in this trial using ESC-derived islets, there is much room for improvement as these results fall short in comparison to islets transplanted from a cadaver donor. When the cells are sourced from a cadaver donor, patients undergo a 90% reduction in insulin administration at the one-year timepoint. The results from this secondary trial indicate improvement in design and further proof of concept that ESC derived islet transplants produce insulin. In future clinical trials, the Kieffer Lab and ViaCyte hope to use these early findings to investigate the optimization of ESC therapy and microencapsulated devices for type 1 diabetes prevention.