25 July 2013
The discovery of a protein that encourages blood vessel growth, and especially ‘bad’ blood vessels – the kind that characterise diseases as diverse as cancer, age-related macular degeneration and rheumatoid arthritis – has been reported in the journal Nature.
The team at the UCL Institute of Ophthalmology discovered the new protein, called LRG1, by screening for mouse genes that are over-expressed in abnormal retinal blood vessels in diseased eyes.
In these diseased retinas the LRG1 protein is expressed by blood vessel endothelial cells, which line blood vessel walls. LRG1 is also present in the eyes of patients with proliferative diabetic retinopathy – a vascular complication of diabetes that can lead to blindness.
The study shows that, in mouse models, LRG1 promotes the growth of blood vessels in a process known as ‘angiogenesis’. Conversely, inhibition of LRG1 in mouse models reduces the harmful blood vessel growth associated with retinal disease.
The authors of the study suggest that blocking LRG1’s activity is a promising target for future therapy.
UCL Business (UCLB) has invested Proof of Concept funding into the development of an antibody therapy against Lrg1. Following this investment the Medical Research Council invested £750k to develop a humanised antibody. UCLB has filed two patent families covering this technology. Angiogenesis is an essential biological process that is required for development, reproduction and the repair of damaged tissues. However angiogenesis also plays a major role in many diseases such as age related macular degeneration (AMD), diabetic retinopathy and cancer where new vessel growth can be harmful.
Vascular endothelial growth factor (VEGF) is a regulator of angiogenesis and the anti-VEGF therapeutics, Lucentis and Eylea, are two of the few blockbuster drugs of recent times with annual sales of $1bn and $800m respectively.
While the anti-VEGF therapies block all angiogenesis Lrg1 is selective for pathogenic angiogenesis. Professor John Greenwood, senior author of the research from the UCL Institute of Ophthalmology said: “We have discovered that a secreted protein, LRG1, promotes new blood vessel growth and its inhibition prevents pathological blood vessel growth in ocular disease.
“Our findings suggest that LRG1 has less of a role in normal blood vessel growth and so may be particularly applicable to ‘bad’ blood vessel growth. This makes LRG1 an especially attractive target for therapeutic intervention in conditions where vessel growth contributes to disease.”
The mechanism through which LRG1 promotes angiogenesis is by modifying the signalling of a multifunctional secreted growth factor called transforming growth factor beta (TGF-beta). TGF-beta regulates both the maintenance of normal healthy blood vessels, and the unwanted growth of harmful blood vessels, but precisely how it promotes two opposing outcomes is a biological paradox.
This study indicates that in the retinal diseases investigated LRG1 production is ‘turned on’ in blood vessels. This causes a switch in TGF-beta signalling away from a normal vessel maintenance pathway towards a pathway that promotes the growth of new harmful blood vessels.
Professor Stephen Moss, senior author from the UCL Institute of Ophthalmology said: “Genetic studies have revealed that the gene that codes for LRG1 is conserved in vertebrates, and this study confirms that mouse and human blood vessels express LRG1.
“We predict, therefore, that abnormal blood vessel growth is also a conserved process and that the role of LRG1 is equally applicable to human pathological angiogenesis.”
UCLB is currently in discussions with potential licensees with regards to the therapeutic being developed.
The research was funded by the Medical Research Council, the Lowy Medical Research Foundation, UCL Business, the Rosetrees Trust, the National Institute for Health Research (NIHR) Biomedical Research Centre at MoorfieldsEyeHospital and UCL Institute of Ophthalmology (who are advising on the translational pathway) and the British Heart Foundation.
For further information about this technology, contact Dr Rachel Hemsley, Senior Business Manager at UCLB. Email: firstname.lastname@example.org Tel: +44 (0)20 7679 9000
Notes for Editors
- ‘LRG1 promotes angiogenesis by modulating endothelial TGF-b signalling’ is published today in Nature. For copies of the paper please contact UCL Media Relations.
- Images from the research are available to journalists from UCL Media Relations.
Link to the research article in Nature
About UCL (University College London)
Founded in 1826, UCL was the first English university established after Oxford and Cambridge, the first to admit students regardless of race, class, religion or gender and the first to provide systematic teaching of law, architecture and medicine.
We are among the world’s top universities, as reflected by our performance in a range of international rankings and tables. According to the Thomson Scientific Citation Index, UCL is the second most highly cited European university and the 15th most highly cited in the world.
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UCL Institute of Ophthalmology
UCL Institute of Ophthalmology is one of the foremost eye and vision research institutes in the world. It operates at the cutting-edge of translational research, delivering new therapies, diagnostic tools and preventive measures to patients suffering from visual impairment or blinding conditions. The combination of the Institute’s research resource with MoorfieldsEyeHospital, which has the largest ophthalmic patient population in the Western World, opens the way for further advances in vision research. The Institute is a recipient of a Queen’s Anniversary Prize for Higher and Further Education, in recognition of outstanding research excellence.
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About the National Institute for Health Research
The National Institute for Health Research (NIHR) is funded by the Department of Health to improve the health and wealth of the nation through research. Since its establishment in April 2006, the NIHR has transformed research in the NHS. It has increased the volume of applied health research for the benefit of patients and the public, driven faster translation of basic science discoveries into tangible benefits for patients and the economy, and developed and supported the people who conduct and contribute to applied health research. The NIHR plays a key role in the Government’s strategy for economic growth, attracting investment by the life-sciences industries through its world-class infrastructure for health research. Together, the NIHR people, programmes, centres of excellence and systems represent the most integrated health research system in the world.
For further information, visit the NIHR website: www.nihr.ac.uk. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
About Rosetrees Trust
Rosetrees Trust is a substantial family foundation established in 1987 that funds life changing medical research. Rosetrees has donated millions of pounds of family money to leading researchers in all the main areas of bio-medical research, including brain and neurological disorders, cancer, cardiovascular disease, imaging, lung damage, nano-technology, regenerative medicine, rheumatology and stroke. Rosetrees currently supports over 200 live medical research projects, with a vision to fund researchers whether established, or young and promising with the potential to become future leaders in their field. Since Rosetrees’ establishment over 25 years ago, in excess of £130 million has been invested in world class research, either from Rosetrees, co donations or the major grants that followed from Rosetrees’ initial support. Rosetrees has a target of generating £1 billion for medical research.
Rosetrees’ unique entrepreneurial philanthropy model sources and selects only the best projects and researchers to support, and then carefully manages the funding throughout the duration. Rosetrees actively seeks trusts and philanthropists to co donate with in order to direct more funds to the best medical research projects, and co donors who fund alongside Rosetrees benefit at no cost from this expertise.
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