Gene Expression & Therapy Group

Current members of the Gene Expression & Therapy Group (GETG)

• Post-doctoral scientist: Dr Robin Mesnage
• Graduate research assistant: Alexia Phedonos
• PhD students: Christina Flouri; Bethany McCloskey

Group research interests

We are a small group but with a diverse range of interests employing cell and molecular analytical approaches to investigate transcriptional and post-transcriptional events that regulate gene expression including in response to various environmental stimuli.

Historically the main research focus of the GETG is the characterisation of genetic regulatory elements with a dominant chromatin remodelling (opening) capability and their exploitation in the development of efficient expression vectors for efficacious and safe biotechnological applications namely protein therapeutic biomanufacturing and human gene therapy.

Recently the GETG has expanded its research work into a new area where molecular profiling (“omics”) tools are employed to investigate the endocrine disruptive capability of low, environmentally relevant doses of key pesticides and other chemical pollutants.

Principal Discoveries and Achievements

• Discovery that transcripts possessing RNA processing (splicing, polyadenylation) defects are arrested at the site of transcription (Custódio et al., 1999).
• Discovery of the first muscle-specific locus control region associated with the human desmin gene locus (Raguz et al., 1998; Tam et al., 2006).
• Discovery of ubiquitous chromatin opening elements (UCOEs) associated with the human HNRPA2B1-CBX3 and TBP-PSMB1 housekeeping gene loci (Harland et al., 2002; Antoniou et al., 2003; Williams et al., 2005; Lindahl Allen and Antoniou, 2007; Saunders et al., 2015).
• Enhanced establishment of and expression from replication episomal plasmid vectors using the HNRPA2B1-CBX3 UCOE (Hagedorn et al., 2013).
• LCR elements are required for stable, tissue-specific gene expression from within replicating episomal plasmid vectors (Chow et al., 2002).
• Biochemistry of splicing-polyadenylation coupling via U2AF65 and CFIm (Antoniou et al., 1998; Millevoi et al., 2002; Millevoi et al., 2006).
• Demonstration of efficacy of UCOE expression cassettes within lentiviral vectors (Zhang et al., 2007; Zhang et al., 2010; Pfaff et al., 2013; Dighe et al., 2014).
• Development of a clinical grade lentiviral vector for gene therapy of the haemoglobinopathies in clinical trials as of 2015 (Miccio et al., 2008).
• Development of bLCR-EF1a based lentiviral vectors for systemic gene therapy of metabolic diseases via red blood cells (Montiel-Equihua et al., 2012)
• Generation of the first primary skeletal myoblast cell model of oculo-pharyngeal muscular dystrophy (OPMD) using desmin LCR expression vectors (Raz et al., 2011).
• Discovery that the HNRPA2B1-CBX3 UCOE stabilises expression from tissue-specific promoter/enhancer elements (Talbot et al., 2010; Brendel et al, 2012).
• Development of human desmin promoter-based lentiviral vectors for muscle gene therapy (Talbot et al., 2010; Jonuschies et al., 2014).
• Confirmation using molecular profiling methods that long-term exposure to an ultra-low dose of Roundup (glyphosate-based) herbicide can lead to liver and kidney damage (Mesnage et al., 2015).

Current projects

1. Advancing plasmid and lentiviral vectors incorporating HNRPA2B1-CBX3 and Rps3 UCOEs for improved protein therapeutic biomanufacturing and for targeting a wide range of tissues including the haematopoietic system, CNS, liver and muscle within a gene therapy context.
2. Development of novel lentiviral vectors for gene therapy of the haemoglobinopathies (thalassaemia and sickle cell disease).
3. Investigating the endocrine disruptive capability of low, environmentally relevant doses of pesticides and other chemical pollutants.