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Development of a Novel Targeted RNAi Delivery Technology in Therapies for Metabolic Diseases

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Technical Report,30 Sep 2015,29 Sep 2016

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University of Massachusetts Worcester United States

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The objective of this project is to develop a novel RNA interference-based therapy for fatty liver diseases and steatohepatitis.Our strategy is to develop a means of targeting siRNA molecules to relevant cells of the liver in order to silence genes that play key roles in inflammatory, metabolic or other pathways that cause disease initiation or progression. The key specific goal of our project is to develop a simple 2 component delivery vehicle for such gene silencing in liver. During this year we have found that covalent coupling of a moiety e.g., cholesterol that promotes entry into cells directly onto the siRNA forming self-delivery sd RNAs rather than directly onto glucan shells that target Kupffer cells is a superb approach. Our priority formulations which we will continue to advance in this project are therefore sd RNAs that can be used alone or encapsulated by glucan shells to selectively target Kupffer cells, as we originally proposed. The data we produced this fourth quarter of year 1 show nearly 100 efficiency of cholesterol-siRNA entering hepatic cells in mice following injection by the subcutaneous route at a dose of 10mgkg. The cholesterol conjugate can be further modified with bioconjugates designed to confer specific cell type delivery and silencing. Thus, by injecting sdRNA alone versus sdRNA encapsulated within glucan shells GeRPs we will be able to confer hepatocyte vs Kupffer cell-specific delivery for target gene silencing and alleviating steatohepatitis.

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