RGM.20.012 – Patient-specific beta-cell replacement therapy using pluripotent stem cells for the treatment of diabetes mellitus
In the Netherlands more than 100,000 people have severe deficiency of insulin-producing beta-cells, such as in type 1 diabetes (T1D), and need insulin therapy to survive. However, despite intensive insulin treatment optimal glycemic control is not achieved resulting in long-term vascular complications and poor quality of life. Thus, diabetes causes a huge financial burden to society. Therefore, there is an unmet clinical and societal need for new therapies to completely normalize glycemic control.
Beta-cell replacement by either pancreas or islet transplantation is the only therapy that normalizes glycemia without a risk of hypoglycemia. However, current therapy is limited by the need of immunosuppression and a shortage of organ donors. Therefore, a renewable source of insulin-producing cells is a key step to develop novel therapies. We focus on pluripotent stem cells (PSC) as the next-generation cell source for beta-cell replacement therapy.
Although we are now able to differentiate PSC into insulin-producing cells, a major drawback to test the long-term functionality of these cells in patients with T1D, is rejection due to alloreactivity for third-party cells and recurrence of autoimmunity. Therefore we propose to generate a proof-of-concept study generating patient-specific iPSC for patients that have severe diabetes due to a total pancreatectomy. Using our current GMP infrastructure, and expertise in human beta-cell biology and clinical beta-cell transplantation, we will: generate clinical-grade iPSC lines for 3 pancreatectomised patients with a total pancreatectomy, apply optimised differentiation protocols, test the functionality and safety of the insulin-producing cells in vitro and in vivo in immunodeficient diabetic mice, and prepare the investigational medicinal product dossier for clinical transplantation. Without allo-and autoreactivity, we can now unequivocally determine the potential of PSC-derived beta-cell replacement therapy. This will set the stage for wider application in patients with T1D.
GMP, insulin, Pluripotent stem cells
|Organisation||Leiden University Medical Center (LUMC)|
|Name||Prof.dr. E. (Eelco) de Koning|