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Abstract

The Hepatitis C virus (HCV) infects over 170 million individuals worldwide and despite the recent addition of DAAs, the current standard of care is limited by long and incomplete genotype coverage. Because the viral genome is comprised of a single strand of RNA and replication occurs strictly within the cytoplasm, HCV is an ideal candidate for therapeutics based upon RNA interference (RNAi). The author has developed TT-034, an RNAi therapeutic which expresses three shRNAs that simultaneously target multiple well-conserved regions of the HCV genome. Intended as a ?one-shot cure?, TT-034 uses an Adeno-Associated Virus (AAV) capsid to deliver the recombinant genome preferentially into hepatocytes; following intravenous administration, greater than 90% of vector was measured liver tissues in biodistribution studies. Once inside the cell, the TT-034 expression cassette uses the cell?s own transcriptional machinery to produce a constantly replenishing pool of shRNA. Characterization of TT-034 demonstrates that as little as 20-200 copies of shRNA per cell, measured by quantitative PCR, was required for complete inhibition of replicon activity. Systemic administration via a single intravenous injection in a non-human primate model resulted in complete transduction of hepatocytes and resulted in the persistent expression of shRNA out to 180 days, the duration of the study. Acute toxicity studies performed in NHPs with clinically relevant doses demonstrate that upwards of 8300 copies of shRNA per cell are produced without hepatocellular toxicity. Follow-on INDenabling, GLP toxicology studies on 520 mice and 80 cynomolgus monkeys showed an excellent safety profile. An open label phase I/II first-in-man dose escalation safety study in chronic HCV patients that have failed the current Standard of Care is currently enrolling.

Biography

David Suhy leads all of Tacere?s therapeutic development programs. As one of the inventors of TT-034, he has directed its development from the drawing board through entry into the clinic. He has held other positions including the Associate Director of R&D at Clontech and as Principal Scientist at Antara Biosciences, developing two molecular diagnostics platforms, based on electrochemistry and RFID tags as chip-based nucleic acid detection modalities. He also led the Target Validation Group at PPD Discovery, a company using genetic suppressor elements to identify ?druggable? genomic targets. He holds a BS in Biochemistry and Biophysics from the University of Pittsburgh, a PhD in Biochemistry, Molecular Biology and Cell Biology at Northwestern University, and conducted Post-doctoral work at Stanford University.