Special Seminar: School of Medicine
- Event Name
- Special Seminar: School of Medicine
- 13 April 2021
- 04:00 pm - 05:00 pm
- Campbelltown Campus
Address (Room): https://uws.zoom.us/j/82781098548
Special Seminar: School of Medicine
- Date: Tuesday 13 April 2021
- Time: 4:00pm
- Speaker: Professor John Greenwood
- Zoom: https://uws.zoom.us/j/82781098548
- Topic: The vasculopathic role of LRG1 in ocular disease and cancer: From discovery to therapeutic targeting
- Host: Distinguished Professor Annemarie Hennessy
Following a transcriptomic analysis of dysfunctional retinal vessels, we discovered a highly induced gene coding for the secreted glycoprotein, leucine-rich alpha-2-glycoprotein 1 (LRG1). We subsequently found that LRG1 contributes to dysfunctional neovascularisation in various models of ocular disease and mediates its vasculopathic effect, in part, by redirecting the TGFβ signalling network and by disrupting pericyte-endothelial cell associations. Lrg1 knockout or blocking the biological activity of LRG1 with an antibody results in attenuation of neovascular growth and leakage in laser-induced choroidal neovascularisation and oxygen-induced retinopathy.
LRG1 is also induced in cancer, and in mouse models loss of LRG1 results in reduced angiogenesis, tumour growth and tumour burden. In addition, LRG1 inhibition increases pericyte coverage of the vasculature and improves vessel function as evidenced by enhanced perfusion, reduced hypoxia and decreases permeability. Vessel normalisation brought about by LRG1 antibody blockade enhances the efficacy of cytotoxic and immune therapies. These data show that LRG1 subverts physiological angiogenesis by promoting dysfunctional vessel growth and that its inhibition has potential clinical utility. To translate this therapeutic approach into the clinic we have developed a humanised and deimmunised therapeutic full-length antibody and Fab fragment and evaluated their safety and toxicology.
In this seminar I will present our work on LRG1 in ocular disease and cancer, provide evidence that it is a major pathogenic factor in disrupting the vasculature, describe the development of a biologic therapeutic and the creation of a UCL spin-out company for its translation into the clinic.
Professor Greenwood trained in physiology at the Institute of Psychiatry, University of London, where his work focused on the structure and function of the blood-brain barrier (BBB) in health and disease. He then moved to the BBB group at King’s College London and after that was awarded the Renee Hock Fellowship at the Institute of Ophthalmology, London. In 2000 he was appointed to the Davson Chair of Biomedical Research and between 2008 and 2016 was Head of the Department of Cell Biology.
The main focus of the Greenwood laboratory is to investigate the role the vasculature plays in the onset and progression of diseases such as uveitis, age-related macular degeneration, diabetic retinopathy, multiple sclerosis (MS), and cancer. The overarching aim of this work is to gain insight into the molecular mechanisms of the vasculature that contribute to the disease process, identify potential therapeutic targets, develop and test therapeutic strategies and eventually translate this into patient trials. His work on the role of the vasculature in inflammatory diseases of the central nervous system has led to a successful clinical trial of statins in MS.
More recently his work has resulted in the identification and characterisation of a novel vascular-disrupting factor and has led to the development of a therapy targeting this protein in ocular disease and cancer.
Major scientific achievements:
- Played a pivotal role in the discovery and description of endothelial cell signalling processes that determine leukocyte migration through the vascular barriers of the brain and retina. This involved establishing the principle of cell adhesion molecule outside-in signalling in endothelial cells that is essential for successful leukocyte migration into the CNS. This work led to the key finding that statins inhibit leukocyte traffic and to a recent successful clinical trial that we conducted on statin therapy in multiple sclerosis (MS). This work is continuing through an investigative clinical trial to evaluate the effect of statins on the structure and function of brain and retinal vasculature using state-of-the-art imaging techniques in human non-diseased and MS subjects. A phase III clinical trial in SPMS patients is also underway.
- In the field of vision research the Greenwood lab has made seminal contributions in regenerative medicine demonstrating for the first time the potential of transplanting immortal human retinal pigment epithelial (RPE) cells to preserve vision in an animal model of age-related macular degeneration (AMD). This work has informed many of the subsequent stem cell and human clinical trials of RPE transplantation as a treatment for AMD.
- Recent work from the Greenwood lab carried out in close collaboration with Professor Steve Moss has led to the discovery of a novel secreted glycoprotein (LRG1) that promotes neovascularization. Inhibition of this glycoprotein inhibits pathogenic neovascularization in the eye and in cancer. This has led to MRC DPFS and UCL Tech funding to develop a therapeutic antibody and initiate clinical trials in these indications. A UCL spin out company (PanAngium Therapeutics) was formed to commercialise the IP. Three patents have been awarded covering this technology.
Name: MOURAD TAYEBI
School / Department: Medicine