Research Highlights

Implantable Niche With Local Immunosuppression for Islet Allotransplantation Achieves Type 1 Diabetes Reversal in Rats

Paez-Mayorga J, Campa-Carranza JN, Capuani S, et al. Nat Commun. 2022;13:7951.

Allogeneic islet cell transplantation has the potential to become an attractive curative therapy for type 1 diabetes.¹ However, the need for allergenic islet transplant recipients to indefinitely take immunosuppressive medications, and the currently poor long-term survival of islet allografts make this therapy replacing daily insulin administration only palatable to those with wide glycemic fluctuations that are difficult to control with even the most thoughtful insulin regimens. Therefore, improvements that could eliminate systemic immunosuppression and prolong islet allograft function would greatly expand the application of this minimally invasive therapy.

In the current study,² Paez-Mayorga et al engineered an islet delivery platform called the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device that simultaneously addresses several issues allogeneic islet cell transplantation currently faces. The device, implantable subcutaneously, was composed of a central cell reservoir where islets were housed and a peripheral U-shaped drug reservoir where immunosuppressive drugs were loaded. Both chambers could also be accessed transcutaneously via 2 silicone ports so that both islets and drugs could be periodically replenished as needed. First, they tested and identified the best biomaterial, namely polyamide, for fabricating the implantable device that resulted in loose and richly vascularized, although thick, fibrous capsules. Second, autologous mesenchymal stem cells were loaded into the cell reservoir where islets were also placed to enhance device integration in the subcutaneous space as well as islet vascularity in the reservoir. Third, the authors tested the drug release kinetics of several clinically relevant immunosuppressants (CTLA4-Ig and antilymphocyte serum) from the drug reservoir and demonstrated that their release did not compromise islet viability or NICHE vascularity. Last, they tested NICHE in 2 streptozotocin-induced diabetes allogeneic islet transplant models: Lewis to F344 rat allogeneic islet transplantation and nonhuman primate allogeneic islet transplantation and showed that with monthly drug loading into the NICHE, the transplanted allogeneic islets were able to maintain euglycemia in most recipients. Importantly, the authors showed that local, unlike systemic, delivery of immunosuppression did not induce measurable systemic immunosuppression as evidenced by preserved populations of circulating lymphocytes and regulatory T cells, and yet effectively attenuated memory T-cell responses and prolonged graft viability.

There are several intriguing features of the NICHE device supporting its future potential as a delivery platform in allogeneic islet cell transplantation. First, the biomaterial used for the drug reservoir can be fine-tuned to the desirable release kinetics of the loaded drugs. This, coupled with its minimally invasive transcutaneous refilling option, would allow individual tailoring of the immunosuppressive cocktails throughout the graft lifespan as needed, for instance, change of the immunosuppressive cocktails over time. Second, the ability to replenish islets is also a highly useful feature of the NICHE device, allowing periodic “top up” of the device, much akin to recharging a battery, with additional islets as the β-cell function wanes over time. This feature would overcome a major obstacle currently facing the islet transplant field. Last, as stem cell-derived insulin-producing cells become a more mature technology,³ one could envision engineering a more standardized NICHE for transplanting such cells that have unique needs for differentiation, vascularization, and immunosuppression in addition to periodic replenishment sustaining a durable function for life-long diabetes control.

Glucagon Receptor Antagonist Volagidemab in Type 1 Diabetes: A 12-week, Randomized, Double-blinded, Phase 2 Trial

Pettus J, Boeder SC, Christiansen MP, et al. Nat Med. 2022;28:2092–2099.

Type 1 diabetes (T1D) is primarily a β-cell dysfunctional and insulinopenic state. However, α-cell dysfunction leading to an increase of postprandial glucagon is also thought to contribute to the difficulty in controlling hyperglycemia in T1D.¹ Therefore, inhibiting glucagon function is thought to improve glycemic control in T1D. One such approach is the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs). These GLP-1RAs act through the GLP-1 receptor to inhibit glucagon secretion while stimulating insulin secretion.² However, in large clinical trials, the use of GLP-1RAs only resulted in a modest reduction of hemoglobin A1c (HbA1c) in T1D patients³ while significantly increasing the rate of hypoglycemia. In contrast, in a phase 1 study in T1D patients, direct glucagon receptor antagonization using a humanized monoclonal glucagon receptor (GCGR) antagonist volagidemab has shown promises in improving glycemic control and reducing daily insulin requirement.⁴

In the current study,⁵ Pettus et al conducted a phase 2 randomized, double-blinded, 12-wk trial in T1D patients comparing escalating doses of volagidemab to placebo in the efficacy of T1D treatment. They enrolled a total of 79 patients into 3 arms and placebo, 35 and 70 mg of volagidemab. Placebo and drugs were all given as weekly subcutaneous injections for 12 wk. In this study, the higher-dose volagidemab (70 mg) did not outperform the lower dose (35 mg) in all efficacy analyses. The 35-mg volagidemab group achieved a −7.95 U reduction of daily insulin dose (primary endpoint) in comparison to the placebo group, although with P = 0.040, this was deemed not achieving the prespecified significance level (P < 0.025). Additionally, they observed a significant decrease in HbA1c (−0.64%) and an improvement in glycemic control by 7-point blood glucose profiles (secondary endpoints). In their post-hoc analysis, they found that HbA1c reduction was most profound in the subset of participants with a higher baseline (≥7.5%). Furthermore, they found that the drug was well tolerated, with the most notable biochemical abnormalities being a transient low-level transaminitis that peaked between weeks 5 and 7 at ~2-fold baseline values, an increase in the mean LDL-cholesterol level that peaked at week 3, and an increase in circulating amino acid concentrations to 1.4- to 2.3-fold, which returned to baseline after drug cessation.

This study provides an appealing new modality, namely GCGR antagonists, to the current treatment landscape for T1D. Mechanistically, blockade of GCGR signaling could further upregulate circulating GLP-1 level,⁶ leading to a positive feedback loop between GCGR and GLP-1 pathways, further augmenting the therapeutic effect of GCGR antagonists. It is important to note that the current study was only designed for a 12-wk treatment/observation period; therefore, it is not clear if the observed therapeutic efficacy would persist during a longer follow-up period. Additionally, it is not clear what the physiological consequences are of the transient transaminitis and increased LDL-cholesterol levels, as well as the increased amino acid levels observed in this study during the treatment period. Additional studies designed to examine the effects of these metabolites on end-organ phenotypes such as hepatic fat deposition will be informative and are currently underway. Last, as the islet transplant field progresses, and allogeneic islets and/or stem cell-derived insulin-secreting cells become available as T1D treatment modalities, it is intriguing to speculate that the efficacy of β-cell replacement may be further augmented by glucagon antagonism, particularly considering the often insufficient β-cell mass available for such replacement therapies.