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Background
The Gissen group use cell and molecular biology approaches to investigate rare genetic disorders with a focus on abnormalities of intracellular trafficking and develop novel therapies to treat these disorders.
Our long-standing interest is in understanding the mechanism of function of a multi-protein tethering complex containing VPS33B and VIPAR. Defects in these two proteins cause a multi-system human disorder Arthrogryposis, Renal Dysfunction and Cholestasis Syndrome (ARC). For this work and other studies we employ cell and animal models of human disease including patient-derived induced pluripotent stem cells (iPSc) that can undergo differentiation into a variety of highly specialised cell types.
Gissen group consists of 3 postdoctoral fellows: Drs Maelle Lorvellec, Leila Nayyer, and Dr Julien Baruteau, 4 research technicians: Danny Kysh, Dany Perocheau, Alice Maestri and Marisa Ofrim. Clinical Fellows Dr Jose Ciancio and Dr Svetlana Tuslova work on the clinical studies at Great Ormond Street Hospital Clinical Research Facility. We regularly joined by the undergraduate and Masters students from UCL and visiting scientists.
Our UCL collaborators are: Professors Adrian Thrasher, Simon Heales, Peter Clayton, Manju Kurian and Paolo De Coppi, Drs Kevin Mills and Philippa Mills (all at the UCL Institute of Child Health), Prof Simon Waddington (UCL Institute for Women's Health).
Our external collaborators include Professor Ian Alexander and Dr Leszec Lisowski (University of Sydney, Australia), Professors Steve Watson and Deirdre Kelly (University of Birmingham, UK), Professors Eamonn Maher and Ludovic Vallier (University of Cambridge, UK), Professor Federico Forneris (University of Pavia, Italy).
Main Interests/Achievements
ARC has an incidence of approximately 1 in 100,000 births. We discovered that deficiencies of VPS33B or VIPAR cause ARC syndrome (Gissen et al, 2004 and Cullinane et al, 2010). Disturbance of apical-basolateral polarity, defects in biosynthesis and function of platelet alpha granules and keratinocyte lamellar bodies are the histological hallmarks of this disease (Smith et al, 2012, Bem et al, 2015, Gruber et al, 2017).
Figure 1. alpha granule biosynthesis dependent on VPS33B-VIPAR complex (from Bem et al, 2015).
Our investigation of the VPS33B and VIPAR interactors and vesicular cargo molecules further defined the pathway that these proteins are involved in and showed abnormalities in collagen homeostasis in ARC (Banushi et al, 2016).
Figure 2. Trafficking of LH3 collagen modifying enzyme from Golgi to collagen-IV carrier dependent on VPS33B-VIPAR (from Banushi et al, 2016).
Figure 3. The role of VPS33B-VIPAR complex in biosynthesis and function of lysosome related organelles (from Rogerson et al, 2017).
Use of disease models for development of treatments in childhood inherited metabolic disorders
In several collaborative projects we are developing AAV based gene therapy for metabolic disorders including ARC syndrome (Hanley et al. 2017) and Argininosuccinic aciduria (Baruteau et al, 2018).
Figure 4. Phenotype correction in the murine model of ARC liver disease using AAV based gene therapy vector (from Hanley at al, 2017).
We are also using induced pluripotent cells to develop models of human disease (Lorvellec et al, 2017 and Little et al, 2018) to test novel therapies.
Grants (current)
European Research Council, MRC, NIHR, Great Ormond Street Hospital Charity
