Development of a Once-Weekly AND Glucose-Responsive Insulin Formulation - PROJECT SUMMARY: An ever-expanding arsenal of insulin variants with customizable pharmacokinetics has enhanced the standard of care for individuals with diabetes. Rapid-acting options are employed alongside mealtime, while long-lasting analogs offer basal support throughout the day. However, developing insulin variants that dynamically adjust bioavailability and potency in response to changes in glucose levels, aligning with real-time therapeutic need, remains an ongoing target. The realization of this long-sought vision of glucose-responsive insulin has the potential to simplify dosing protocols and improve glycemic control, effectively mitigating both hyperglycemic and hypoglycemic episodes and their associated health complications; insulin therapy would instead be ready to respond to elevated blood glucose levels as needed. Meanwhile, the clinical impact of once-weekly antidiabetic medications (e.g., GLP-1 analogs) underscores the benefits of reduced dosing frequency in enhancing therapeutic adherence. While once-weekly insulin is a near-term clinical possibility, the development of glucose-responsive insulin has proven more elusive. In this project, we present a platform aimed at achieving both week-long AND glucose-responsive insulin from a single injection. Our preliminary approach involved chemically modifying insulin with a novel glucose binder in combination with a dendrimer carrier. This approach coupled electrostatic complexation with glucose-sensing dynamic-covalent bonding to create a subcutaneous nanocomplex insulin depot. Early results support the ability of this depot to respond to glucose challenge by promptly increasing serum insulin levels, as well as its ability to sustain function for at least a week in a diabetic swine model. However, the translation of this technology to clinical use may encounter certain challenges. This proposal focuses on addressing these anticipated hurdles and further validating the platform. One key concern is that chemical modification of insulin can reduce its potency and receptor binding affinity. To mitigate this issue, we will explore alternative linkers and conjugation strategies to minimize the impact of chemical modifications on insulin function. Additionally, the dendrimer carrier presents potential risks related to toxicity, limited biodegradation, and clearance. Drawing inspiration from degradable cationic carriers commonly used in gene delivery, we will investigate versions that offer improved biocompatibility and clearance. We will validate optimized formulations for their efficacy in diabetic rodents and assess their glucose-specific potency in rodent glucose-clamped models. Finally, we will confirm therapeutic function of our improved platform in a human-sized diabetic swine model, both in response to simulated meals and in the context of long-term blood glucose control with once-weekly dosing. Our innovative strategy to develop a week-long AND glucose-responsive insulin depot holds promise as a clinically viable product with direct impact on the lives of a rapidly growing population of individuals with all forms of diabetes.
