RNA interference (RNAi) is a biological mechanism wherein double-stranded RNAs (siRNAs) can be used to reduce expression of target proteins, and has emerged as a promising therapeutic strategy for the treatment of many diseases, including inflammatory diseases and malignancies. However, development of clinical applications of RNAi therapy has been hindered by the lack of clinically suitable, safe, and effective delivery vehicles. If such technology could be developed, a transformative advance in medicine would result. Macrophages are particularly attractive targets for RNA interference therapy because they promote pathogenic inflammatory responses in diseases such as rheumatoid arthritis, atherosclerosis, and diabetes. Thus, siRNA delivery systems capable of targeting immune cells present a promising therapeutic approach for the treatment of these and numerous other major human diseases. Despite significant recent progress in the delivery of small interfering RNA (siRNA) to immune cells, several major challenges to the clinical translation of siRNA as therapy remain. Thus, this proposal seeks to develop a platform for the delivery of small interfering RNA to immune cells (e.g., macrophages) and to demonstrate the utility of this technology in the treatment of inflammation-related diseases. Our laboratory has recently developed a novel siRNA delivery system based on glucan microparticles. We have demonstrated that these ?-1,3-D-glucan-encapsulated siRNA particles (GeRPs) can potently silence genes in mouse macrophages in vivo. A major advance would be to simplify this complex, multi-component system into a single component system that when mixed with siRNA forms a delivery vehicle.
Aim 1 of this proposal will develop a technology that can efficiently deliver siRNA to immune cells. A small library of particles with tunable properties will be developed by the chemical modification of the glucan particles with a variety of functionalities.
Aim 1 will also optimize the modified particles for delivery of siRNA to macrophages in vivo.
Aim 2 will test the ability of chemically-conjugated glucan particles to mediate gene silencing in inflammatory macrophages and to ameliorate disease in mouse models of insulin resistance and type 2 diabetes. It will evaluate the in vivo biodistribution of the particles following administration to mice and quantify the ability of siRNA-loaded particles to silence inflammatory genes. Finally, it will demonstrate the therapeutic potential of the particles in the treatment of obesity-related diseases. The development of novel delivery technologies combined with evaluation of these systems in relevant disease models will be critical steps toward developing clinical therapies based on RNAi-mediated gene silencing.

Public Health Relevance

RNA interference (RNAi)-based gene silencing has emerged as a promising therapeutic strategy for the treatment of many diseases. Unfortunately, translation of the potential of small interfering RNA (siRNA) into the clinic is limited by the lac of safe and effective delivery systems. This project seeks to develop a novel method for delivering siRNA specifically to the cells which mediate inflammation in many important human diseases including diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32DK098879-01
Application #
8525783
Study Section
Special Emphasis Panel (ZDK1-GRB-R (J1))
Program Officer
Castle, Arthur
Project Start
2013-02-12
Project End
2016-02-11
Budget Start
2013-02-12
Budget End
2014-02-11
Support Year
1
Fiscal Year
2013
Total Cost
$49,214
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Aouadi, Myriam; Vangala, Pranitha; Yawe, Joseph C et al. (2014) Lipid storage by adipose tissue macrophages regulates systemic glucose tolerance. Am J Physiol Endocrinol Metab 307:E374-83