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In vitro characterization of the activity of PF-05095808, a novel biological agent for hepatitis C virus therapy.

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 three short hairpin RNAs (shRNAs) 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 to 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 quantitative PCR (qPCR) assay was developed. The number of shRNA molecules needed to drive antiviral activity proved to be independent of the vector delivery system used for PF-05095808 administration. The emergence of resistant variants at the target site of one shRNA was characterized. 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 both support antiviral activity consistent with an RNA interference mechanism and demonstrate the potential of PF-05095808 as a therapeutic agent for chronic HCV infection.

SUBMITTER: Lavender H

PROVIDER: S-EPMC3294929 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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In vitro characterization of the activity of PF-05095808, a novel biological agent for hepatitis C virus therapy.

Lavender Helen H Brady Kevin K Burden Frances F Delpuech-Adams Oona O Denise Hubert H Palmer Amy A Perkins Hannah H Savic Boris B Scott Sarah S Smith-Burchnell Caroline C Troke Phil P Wright J Fraser JF Suhy David D Corbau Romu R

Antimicrobial agents and chemotherapy 20111227 3

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 three short hairpin RNAs (shRNAs) 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 ...[more]

PMID: 22203606

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Project description:BackgroundRapid improvements in hepatitis C virus (HCV) therapy have led to the approval of multiple oral direct-acting antiviral (DAA) regimens by the U.S. Food and Drug Administration (FDA) for treatment of chronic HCV infection.PurposeTo summarize published literature on the efficacy and safety of oral DAAs for treatment of persons with chronic HCV infection.Data sourcesMEDLINE and EMBASE from inception through 1 November 2016.Study selection42 English-language studies from controlled and single-group registered clinical trials of adults with HCV infection that evaluated at least 8 weeks of an FDA-approved interferon-free HCV regimen that included at least 2 DAAs.Data extractionTwo investigators abstracted data on study design, patient characteristics, and virologic and safety outcomes sequentially and assessed quality independently.Data synthesisSix DAA regimens showed high sustained virologic response (SVR) rates (>95%) in patients with HCV genotype 1 infection without cirrhosis, including those with HIV co-infection. Effective treatments for HCV genotype 3 infection are limited (2 DAA regimens). Patients with hepatic decompensation, particularly those with Child-Turcotte-Pugh class C disease, had lower SVR rates (78% to 87%) than other populations. The addition of ribavirin was associated with increased SVR rates for certain DAA regimens and patient groups. Overall rates of serious adverse events and treatment discontinuation were low (<10% in the general population); regimens that included ribavirin had more mild or moderate adverse events than those without.LimitationsTwenty-three studies had moderate risk of bias (10 were open-label single-group trials, 11 had limited information on concealment of the allocation scheme, and 5 had selective outcome reporting). All but 1 of the studies were industry-funded. Heterogeneity of interventions precluded pooling.ConclusionMultiple oral DAA regimens show high rates of safety, tolerability, and efficacy for treatment of HCV genotype 1 infection, particularly among persons without cirrhosis.Primary funding sourcePatient-Centered Outcomes Research Institute. (PROSPERO: CRD42014009711).

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In vitro characterization of the activity of PF-05095808, a novel biological agent for hepatitis C virus therapy.

Publications

In vitro characterization of the activity of PF-05095808, a novel biological agent for hepatitis C virus therapy.

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