Objective
Islet beta cells play an essential role in glucose homeostasis by releasing insulin to lower the blood glucose level. In type 1 diabetes (T1D), beta cells are lost from autoimmune attack. Recent studies have highlighted the involvement of beta cells in autoimmunity development in T1D, and suggested that stressed beta cells could incite immune cells to initiate or amplify immune assault early on in T1D development. New therapeutic strategies that can ameliorate beta cell stress are expected to temper down autoimmunity on beta cells to prevent T1D or to slow disease progression. Currently there is no anti-diabetic drug that selectively targets beta cells to relieve beta cell stress. Our objective is to develop therapeutic products to prevent or slow the course of T1D, focusing on devising novel targeted delivery of small molecules for protecting beta cells.
Background Rationale
Islet beta cells only constitutes <2% of pancreas mass. How to maximize the therapeutic efficacy on this minute population of endocrine cells remains a challenge for the next generation precision medicine. The potential benefits of targeted drug delivery to islet beta cells can not be overstated. Localized drug enrichment in the islets enhances the therapeutic efficacy, minimize the potential side effects of systemic drug exposure, and improve the therapeutic index of beta-tropic agents. It has long been known that the insulin granule of islet beta cells contains abundant zinc. The high zinc concentration in the insulin granule provides a unique and abundant biomarker for beta cell targeting. We propose developing zinc-tropic agents and apply them for targeted drug delivery to beta cells.
Description of Project
Islet beta cells play an essential role in glucose homeostasis by releasing insulin to lower the blood glucose level. In type 1 diabetes (T1D), loss of beta cells from autoimmune attack represents a primary event leading to high blood glucose and the associated complications. Recent studies have highlighted the involvement of beta cells in autoimmunity development in T1D, and suggested that stressed beta cells could incite immune cells to initiate or amplify immune assault early on in T1D development. New therapeutic strategies that can ameliorate beta cell stress are expected to temper down autoimmunity on beta cells to prevent disease progression. To this end, we plan to develop a beta cell targeted drug delivery platform to selectively deliver small molecule drugs to pancreatic islets to relieve beta cell stress. After preparing these compounds by chemical syntheses, we will evaluate their activity in cultured beta cells and characterize their pharmacokinetics and biodistribution in vivo. Once we identify lead compounds with the desired properties, we will apply them to a diabetic mouse model to prevent or treat T1D. In addition, we plan to evaluate the activity of these molecules in protecting human islets in vivo after implantation. If successful, the study will produce novel compounds with the therapeutic potential for treating T1D.
Anticipated Outcome
The goal of this proposal is to develop a drug delivery platform to target islet beta cells, and to apply the platform to enable selective and efficient delivery of a small chemical chaperone to pancreatic islets to mitigate beta cells stress and inflammation, and to curb autoimmune attack on beta cells during pre-diabetes or the early stage of Type 1 Diabetes (T1D) development. If successful, the strategy may offer a new therapy for preventing T1D or delaying T1D progression.
Relevance to T1D
This proposal aims to develop a novel class of beta cell targeted compounds to relieve beta cell stress in order to prevent or treat type 1 diabetes. The proposed project is responsive to the Disease Modifying Therapies (DMT) outlined in the Cures Mission set forth by JDRF. Specifically, we plan to develop therapeutic products to prevent or slow the course of T1D.