Our Technology

Overview

Discovery of the RNA interference (RNAi) pathway and advances in the engineering of sequence-specific nucleases have provided the means for powerful and specific disabling of genes. These advances led to considerable enthusiasm for use of gene therapy to counter viral infections, such as are caused by persistence of hepatitis B virus (HBV) and human immunodeficiency virus type 1 (HIV-1). The focus of the AGTRU has been on optimising use of RNAi activators and derivatives of transcription activator-like effectors (TALEs) to inhibit viral proliferation. Development of suitable vectors for delivery of antiviral sequences to infected cells is also an active field of investigation within the unit.

RNAi

We previously designed artificial RNAi-activating Pol II expression cassettes that generate effective anti-HBV monocistronic and polycistronic mimics of natural primary microRNAs (pri-miRs). To deliver these sequences to the liver and achieve sustained inhibition of viral replication, our current focus is incorporation of the expression cassettes into recombinant Helper Dependent Adenoviruses (HD Ads), lentiviruses and adeno associated viruses (AAVs).

Gene editing

Advancing therapeutic use of sequence-specific mutagenic transcription activator-like effector nucleases (TALENs) is another active field of investigation in our unit. The approach is particularly appealing as it offers the means to inactivate the problematic episomal covalently closed circular DNA (cccDNA) intermediate of HBV replication. Since licensed anti-HBV drugs have a post transcriptional mechanism of action, disabling cccDNA is potentially of therapeutic benefit. TALENs with cognate sequences in the surface or core open reading frames (ORFs) efficiently disrupted cccDNA sequences at the intended sites and suppressed viral replication.