Development of clinical applications of RNAi therapy has been hampered by a number of hurdles. The most difficult roadblock has been achieving safe, effective delivery of siRNA to specific target cell types or tissues. We thus seek to develop reliable technology for oral siRNA delivery, with the goal of applying it as rapidly as possible to therapies which will have maximal impact on human health. RNAi-based therapies targeting macrophages could transform the practice of medicine for numerous major human diseases including type 1 and 2 diabetes, atherosclerosis, arthritis and inflammatory bowel disease. We have previously described a novel siRNA delivery system based on B1,3-D-Glucan-encapsulated siRNA Particles (GeRPs) as efficient oral delivery vehicles that potently silence genes in mouse macrophages in vitro and in vivo. We propose to develop this technology as a novel therapeutic approach for these and other diseases. We propose to quantitate and optimize the delivery of siRNA encapsulated within GeRPs to macrophages in multiple tissues. We will also improve GeRP formulations to maximize potency and duration of target gene silencing. Finally, we will test the ability of GeRP-mediated gene silencing in inflammatory macrophages to ameliorate disease in mouse models of insulin resistance and type 2 diabetes. These will be critical steps toward developing clinical therapies based on RNAi-mediated gene silencing in macrophages. The impact of developing a vehicle for orally delivering siRNA to macrophages in humans would be potentially huge given the large number of major diseases that could be targeted.

Public Health Relevance

The use of RNA interference (RNAi) based gene silencing holds great promise as a clinical therapy for many diseases, but such applications face many hurdles including reliable methods for delivery to target tissues and organs. We have developed a novel microparticle technology for oral RNAi delivery to macrophages in living animals and demonstrated in vivo gene silencing and amelioration of inflammation.We propose here to develop this method as a clinical strategy for treating a number of important diseases in which macrophage-mediated inflammation plays a role including type 1 and 2 diabetes, atherosclerosis, arthritis and inflammatory bowel diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK085753-05
Application #
8538948
Study Section
Special Emphasis Panel (ZRG1-BCMB-A (51))
Program Officer
Abraham, Kristin M
Project Start
2009-09-21
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$1,150,827
Indirect Cost
$451,235
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
Negrin, Kimberly A; Roth Flach, Rachel J; DiStefano, Marina T et al. (2014) IL-1 signaling in obesity-induced hepatic lipogenesis and steatosis. PLoS One 9:e107265
Amano, Shinya U; Cohen, Jessica L; Vangala, Pranitha et al. (2014) Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation. Cell Metab 19:162-71
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
De Jesus, Magdia; Ostroff, Gary R; Levitz, Stuart M et al. (2014) A population of Langerin-positive dendritic cells in murine Peyer's patches involved in sampling ?-glucan microparticles. PLoS One 9:e91002
Jourdan, Tony; Godlewski, Grzegorz; Cinar, Resat et al. (2013) Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. Nat Med 19:1132-40
Czech, M P; Tencerova, M; Pedersen, D J et al. (2013) Insulin signalling mechanisms for triacylglycerol storage. Diabetologia 56:949-64
Guo, Chang-An; Kogan, Sophia; Amano, Shinya U et al. (2013) CD40 deficiency in mice exacerbates obesity-induced adipose tissue inflammation, hepatic steatosis, and insulin resistance. Am J Physiol Endocrinol Metab 304:E951-63
Aouadi, Myriam; Tencerova, Michaela; Vangala, Pranitha et al. (2013) Gene silencing in adipose tissue macrophages regulates whole-body metabolism in obese mice. Proc Natl Acad Sci U S A 110:8278-83
Czech, Michael P; Aouadi, Myriam; Tesz, Gregory J (2011) RNAi-based therapeutic strategies for metabolic disease. Nat Rev Endocrinol 7:473-84
Tesz, Gregory J; Aouadi, Myriam; Prot, Matthieu et al. (2011) Glucan particles for selective delivery of siRNA to phagocytic cells in mice. Biochem J 436:351-62