Benitec Biopharma hepatitis C therapeutic pre-clinical results released

Benitec Biopharma (ASX: BLT) is in a long term gene silencing using DNA-directed RNA interference (ddRNAi) for human therapeutics. The Company’s primary therapeutic program focuses on human immunodeficiency virus (HIV). Its other projects are in the area of infectious diseases and cancer.

Benitec Biopharma hepatitis C therapeutic pre-clinical results released
Monday, January 09, 2012
by Christine Feary

Benitec Biopharma (ASX: BLT) has received pre-clinical results on the use of the company’s gene silencing technology to develop a therapeutic for hepatitis C viral (HCV) infection.

HCV infection is a leading cause of liver disease, with figures from the World Health Organisation showing that about 170 million people are chronically affected.

The figures showed that there are approximately 350,000 deaths from HCV-related liver disease each year.At present, therapy typically involves extended dosing of between 24 and 72 weeks duration, with low tolerability and only modest effects.

Results from pre-clinical studies by researchers at Pfizer and Tacere Therapeutics have been published online in the American Society of Microbiology’s journal, Antimicrobial Agents and Chemotherapy.

The pre-clinical trials showed extremely positive results for ddRNAi molecule PF-05095808.

This molecule has been specifically designed to achieve transduction of all liver cells in the liver without causing cell damage.

Importantly, there was no evidence of cytotoxicity nor of induction of the interferon response associated with the administration of the molecule.

It was also shown to be highly effective at inhibiting the commonly circulating clinical isolates of HCV, with the ability to eliminated resistance to the molecule using three shRNA sequences.

The studies indicated that the molecule is able to target commonly circulating strains of HCV.

The report concluded that the molecule represents the prototype of a new approach to HCV therapy, with a single dose that can be administered alone or in combination with other anti-HCV agents.

According to the report, “These studies demonstrated the PF-05095808 delivers sequence-specific antiviral activity in the absence of overt cytotoxicity.”A clinical trial is expected to follow, with Tacere confirming its commitment to progressing the program, for which it has an exclusive sub-license from Benitec.

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The American Society of Microbiology’s journal, Antimicrobial Agents and Chemotherapy.

In vitro characterization of the activity of PF-05095808 a novel biological agent for Hepatitis C Virus therapy
Helen Lavender, Kevin Brady, Frances Burden, Oona Delpuech-Adams, Hubert Denise,
Amy Palmer, Hannah Perkins, Boris Savic, Sarah Scott, Caroline Smith-Burchnell,
Phil Troke, J. Fraser Wright, David Suhy, and Romu Corbau Antimicrob.

Agents Chemother. AAC.05357-11; published ahead of print 27 December 2011 doi:10.1128/AAC.05357-11

ABSTRACT
PF-05095808 is a novel biological agent for chronic Hepatitis C Virus (HCV) therapy. It comprises a recombinant Adeno-associated virus (AAV) DNA vector packaged into an AAV serotype 8 capsid. The vector directs expression of 3 short hairpin (sh) RNAs targeted to conserved regions of the HCV genome. These shRNAs are processed by the host cell into the small interfering RNAs which mediate sequence specific cleavage of target regions. For small molecule inhibitors the key screens needed to assess in vitro activity are well defined, we developed new assays to assess this RNA interference agent and so understand its therapeutic potential. Following administration of PF-05095808 or corresponding synthetic shRNAs, sequence specific antiviral activity was observed in HCV replicon and infectious virus systems. To quantify the numbers of shRNA molecules required for antiviral activity in vitro and potentially also in vivo, a universal qPCR assay was developed. The number of shRNA molecules needed to drive antiviral activity proved independent of the vector delivery system used for PF-05095808 administration. The emergence of resistant variants at the target site of one shRNA was characterised. A novel RNA cleavage assay was developed to confirm the spectrum of activity of PF-05095808 against common HCV clinical isolates. In summary, our data supports both antiviral activity consistent with an RNA interference mechanism and demonstrates the potential of PF-05095808 as a therapeutic agent for chronic HCV infection.

Abstract
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