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 tamp 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 disease modifying therapy. 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. We recently succeeded in developing a small molecule scaffold termed Beta cell Targeting Motif (BTM), and applied BTM to prepare a beta cell targeted prodrug to prevent type 1 diabetes in a preclinical mouse model. Understanding the precise mechanisms of action of BTM prodrugs in beta cell targeting and in beta cell protection will offer us insights to engineer even better disease modifying therapies for preventing, treating or even curing T1D.
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 tamp down autoimmunity on beta cells to prevent disease progression. To this end, we recently developed a beta cell targeted drug delivery platform to selectively deliver a small molecule drug to pancreatic islets to relieve beta cell stress. Moreover, when combined with an immune modulation antibody, the beta cell targeted prodrug drastically reduced diabetes incidence in a preclinical T1D mouse model. This proposal aims to investigate the mechanisms of action of the beta cell targeted prodrug in beta cell targeting, in beta cell protection, and in diabetes prevention. In addition, we will study the activity of the prodrug in human beta cells.
Anticipated Outcome
The goal of this proposal is to refine a drug delivery platform to target islet beta cells, and to understand the molecular mechanisms of the targeted prodrug in mitigating 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 study will offer fresh insights to guide future development or improvement of more effective disease modifying therapy for preventing and treating T1D.
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 BT1D. Specifically, we plan to develop therapeutic products to prevent, delay or even stop the course of T1D.