A New Era in Islet Transplantation: Stem Cell-Derived and Gene-Edited Islet Therapies

Type 1 diabetes mellitus (T1DM) is characterized by absolute insulin deficiency resulting from the autoimmune destruction of pancreatic β-cells [1,2]. Restoring functional and immunetolerant β-cells represents the ideal therapeutic strategy for treating patients with T1DM. Islet transplantation offers a potential cure; however, its widespread use is limited by donor organ shortages and adverse effects of lifelong immunosuppressive therapy, which include renal impairment and infection [3,4].

Two groundbreaking studies published in the New England Journal of Medicine in 2025 marked a turning point and presented complementary strategies to overcome these barriers (Fig. 1) [5,6]. Reichman et al. [6] evaluated zimislecel, an allogeneic stem cell-derived islet cell therapy, in a multi-center phase 1–2 study that involved 14 participants with T1DM. Participants received either half or full doses of cells infused into the portal vein, along with immunosuppressive therapy. Engraftment was successful in all patients, as evidenced by detectable post-infusion C-peptide levels. Among the full-dose recipients, 83% achieved insulin independence at 1 year, and all were free from severe hypoglycemia. The mean glycosylated hemoglobin level decreased by 1.81%, and the time in the target glucose range exceeded 90%. Most adverse events were mild-to-moderate; however, two deaths occurred, one of which was due to cryptococcal meningitis linked to immunosuppression that suggests risks related to immune suppression. This trial nevertheless represents a milestone in regenerative medicine and confirms that zimislecel provides a renewable, standardized, and applicable β-cell source that overcomes the limitations of cadaveric islet supply.

Fig. 1.

Addressing the limitations of islet transplantation. The use of hypoimmune platform (HIP) islet cells (top) and zimislecel (bottom) offers potential solutions to key challenges in conventional islet transplantation. HIP islets are genetically modified allogeneic islets engineered to evade the innate immune response by deleting human leukocyte antigen (HLA) class I and II expression and overexpressing CD47, eliminating the need for immunosuppressive therapy. Zimislecel consists of insulin-producing cells derived from embryonic stem cells, addressing the issue of donor scarcity. T1DM, type 1 diabetes mellitus; CRISPR, clustered regularly interspaced short palindromic repeats.

Carlsson et al. [5] reported a first-in-human proof-of-concept study, in which gene-edited human islets were transplanted into a patient with long-standing T1DM, notably without immunosuppressive therapy. These islets were engineered to lack human leukocyte antigen (HLA) class I and II expression and overexpress CD47, thereby creating a hypoimmune platform (HIP) islets capable of evading both adaptive and innate immune responses. In this single-participant trial, the patient presented detectable glucose-responsive C-peptide secretion by week 4, which persisted for 12 weeks. Importantly, the hypoimmune islets evaded T-cell, natural killer (NK)-cell, macrophage, and antibody-mediated rejection, which reflects a level of immune protection that has not been achieved thus far with partially edited or wild-type islets. Positron emission tomography-magnetic resonance imaging confirmed the successful engraftment and function of the forearm muscle, thereby providing a less invasive alternative to traditional portal vein infusion. This approach effectively eliminates the need for systemic immunosuppression, thus offering a safer and potentially scalable strategy for β-cell replacement. Collectively, these two studies provide compelling evidence that cellular therapies for T1DM are shifting from theory to clinical practice. Zimislecel reflects the applicability of stem cell-derived β-cells, whereas the gene-edited HIP islets illustrates how synthetic immunology may enable rejection-free engraftment.

Rapid advancements in digital technology have transformed precision care for patients with T1DM [7]. Continuous glucose monitoring systems, insulin pumps, activity trackers, and food recognition applications enable real-time access to patient lifelog data. Combined with artificial intelligence, these technologies have shown potential for facilitating physiological insulin replacement strategies [8,9]. Consequently, the interest in islet transplantation has declined in recent years. Moreover, xenotransplantation, which was previously considered a promising alternative for islet replacement, has encountered safety concerns after a recent heart xenotransplantation trial, in which the recipient died after a cytomegalovirus infection [10].

In this context, the promising results of two recent studies have revived interest in islet transplantation as an important therapeutic option. Islet transplantation has shown particular benefits in patients with hypoglycemic unawareness, and current guidelines recommend this treatment modality for patients with T1DM who experience unstable glycemic control and recurrent level 3 hypoglycemia [11,12]. Though not fully understood, the presence of co-transplanted α-cells is thought to contribute to this benefit [4]. In the study by Reichman et al. [6], no severe hypoglycemic events occurred during the study period, despite the fact that the study included participants with such histories. The authors reported that zimislecel consists of β-like cells and non-β-like endocrine cells, the proportion of which is similar to the composition of natural islets. The measurement of serum glucagon levels would provide valuable insights into the underlying mechanism.

In the study by Carlsson et al. [5], the gene-edited islets were transplanted into the forearm muscle. Although the portal vein and omentum have traditionally been the most common sites for islet transplantation, only a limited number of successful cases of islet implantation in the forearm muscle have been reported. This study adds to the evidence that supports the forearm as a feasible, retrievable, and safe alternative site for islet engraftment, with confirmation of graft function [13]. CD47 expression is a known mechanism by which cancer cells evade the innate immune system. The long-term safety of gene-edited HIP islets that express CD47 has yet to be fully established. Using the forearm as a transplantation site offers a safer and more accessible platform for monitoring and addressing potential safety concerns.

Several critical questions remain unanswered as this field progresses. The key uncertainties include whether gene-edited islets can be applied beyond proof-of-concept case reports, whether stem cell-derived therapies can ultimately obviate the need for immunosuppression, and the long-term safety profiles of these novel interventions. Nonetheless, despite these challenges, recent studies represent an important advance in diabetes research and mark the transition of β-cell replacement strategies from aspiration toward a realistic prospect of achieving a cure for T1DM.