Engineering hypoimmune stem cell-derived beta cells

Abstract

In type 1 diabetes (T1D), autoimmune targeting destroys insulin-producing β cells in the pancreas, creating a chronic state of insulin deficiency. Islet transplantation presents a regenerative cell therapy approach that can re-establish insulin production and intrinsic glycemic control. However, islet transplantation is currently limited by a lack of cadaveric human islet donors and a requirement for life-long immune suppression following transplant. Developments in stem cell maturation and differentiation protocols have enabled production of insulin-producing cells ‘on demand’, thereby addressing the pancreatic donor tissue shortage. Continued reliance on immune suppression to avoid graft rejection, however, can result in opportunistic infection and malignancy, thus remaining a major obstacle for wide-spread application of insulin-producing β cell transplantation. As such, there has been significant interest in identifying alternative strategies for avoiding graft rejection without immune suppression including encapsulation and co-transplantation of accessory immunomodulating cells. However, these approaches are limited by incomplete immune isolation as well as concerns over maintenance of effector function and graft survival in vivo, respectively. Genetically engineering hypoimmune stem cell-derived β cells has thus emerged as a promising strategy for improving islet transplantation outcomes. These approaches leverage our understanding of pathways involved in immune regulation to selectively protect the transplanted insulin-producing cells without affecting systemic immune function. This review will summarize recent bioengineering approaches for generating hypoimmune stem cell-derived β cells. It will also discuss relevant safety concerns and potential genetic targets for future investigation that take inspiration from the development of immune evasive primary islets and chimeric antigen receptor (CAR) T cells.

1. Introduction

Type 1 diabetes (T1D) is a chronic disease that is characterized by autoimmune targeting and destruction of pancreatic β cells resulting in absolute insulin deficiency [1, 2]. T1D constitutes approximately 2–10% of all diabetes cases globally, although the incidence is increasing annually and estimates of prevalence in Europe are greater than 15% [3–5]. The current standard of treatment for the past century, exogenous insulin injection, does not prevent progression of diabetes and predisposes patients to hypoglycemic events [6, 7]. There is thus a significant interest in islet transplantation as an alternative and regenerative therapy option for T1D.

Islet transplantation, however, is currently limited by a requirement for life-long immune suppression which increases the risk of cancer and development of serious infection [8]. This was emphasized by a recent clinical trial (ClinicalTrials.gov identifier: NCT04786262) where all β cell transplant recipients experienced significant adverse effects related to immunosuppression [9]. Additionally, a lack of donor tissue limits the application of islet transplantation to patients with severe hypoglycemic unawareness [10]. Research on the development and maturation of pancreatic progenitors into islet cells has enabled the differentiation of stem cells into insulin-producing β cells [11]. This advancement promises to provide a theoretically infinite supply of β cells, thereby overcoming the donor shortage and making this therapy option more feasible.