Sa1015 Long Duration of Effect From RNAI Therapeutic to Treat Chronic Hepatitis B Virus Infection Correlates With Persistence of the Phosphorylated Guide Strand

Abstract

Chronic hepatitis B virus (HBV) infection is a major disease for which there remains an unmet medical need. Current therapies for chronic hepatitis B include reverse transcriptase inhibitors and interferon. These therapies either require life-long administration or have significant side effects and limited efficacy. We have taken a novel approach toward the treatment of chronic hepatitis B by developing an siRNA-based therapeutic. In contrast to current therapies, our approach has the promise of significantly decreasing viral protein load which is primarily responsible for disease progression. In our formulation, liver-tropic cholesterol-conjugated siRNAs against HBV (chol-siHBVs) are co-injected intravenously with a reversibly masked, hepatocyte-targeted melittin-like peptide (NAG-MLP). Co-injection of chol-siHBVs and NAG-MLP results in multi-log repression of viral RNA, proteins and viral DNA with long duration of effect in transient and transgenic mouse models of chronic HBV infection, without toxicity. Using a hybridization/HPLC-based method of detection, we are able to correlate the degree of repression of the virus with the amount of the active form of the siRNA guide strand in the liver. In addition, this form of the guide strand can be detected up to one month after a single administration, correlating with the duration of effect. High efficacy, a long duration of effect and establishment of a robust pharmacokinetic/ pharmacodynamic relationship in the liver suggest co-injection of NAG-MLP and cholsiHBVs holds great promise as a novel therapeutic for chronically HBV infected patients.