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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 2018

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University of Massachusetts Medical School Worcester United States

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Our objective 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 nonalcoholic steatohepatitis NASH initiation or progression. During this project we discovered that covalent coupling of a moiety e.g., cholesterol or GalNAc that promotes entry into cells directly onto the siRNA forming self-delivery sd RNAs is a superb approach. During this past year we have focused on cholesterol covalently attached to the modified siRNA to determine efficiency for gene silencing in mice. Importantly, we have chemically modified the siRNA segment of the therapeutic to attenuate nuclease-mediated degradation, immune responses and toxicity and prolong gene silencing for weeks after one injection. We found both hepatocytes and Kupffer cells are well targeted by these formulations, with high efficiency and tissue specificity in gene silencing after single subcutaneous injections. We have identified superb target genes TAZ and MCT1 for NASH, and high potency sdRNAs against these genes after exhaustive screening of sdRNA sequences. We have accomplished the silencing of TAZ selectively in liver with a potent Chol-sdRNA and a potent GalNAC-sdRNA, a major milestone. Importantly, we have now also reached our key milestone of the project, demonstrating a strong beneficial effect of Chol-sdRNA in a NASH mouse model.

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  • Genetic Engineering and Molecular Biology

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