Dr. Xinhua Shu is a Rosetrees Trust-funded researcher who, with his team at Glasgow Caledonian University, is investigating new treatments for age-related macular degeneration (AMD). AMD is the commonest cause of registered blindness in the developed world, with a global impact estimated to rise to 196 million people by 2020.
Previously, Dr. Shu received funding from Rosetrees to work on retinitis pigmentosa (RP). This is an inherited disease that causes degeneration of the light-sensitive photoreceptor cells in the retina of the eye, leading to progressive loss of vision and ultimately blindness. Dr. Shu investigated possible protective effects of gypenosides, chemical compounds found in Gynostemma pentaphyllum, a plant common to South-East Asia, and how they might shield particular cells in the eye from oxidative stress caused by free radicals, damaging molecules released in the condition (published in Food and Chemical Toxicology). It is hoped that these gypenosides may offer therapeutic potential to patients suffering with RP.
As a result of his RP project, Dr. Shu secured further funding from Rosetrees to work on AMD. It is known that AMD involves the build-up of cholesterol deposits in the retina. Dr. Shu and his team published in Human Molecular Genetics, identifying the part played by a particular cell protein known as TSPO in the removal of cholesterol from the retinal pigment epithelium (RPE), the specialised layer of cells that lies behind the photoreceptor cells. Dr. Shu is now taking his research into new areas with his latest hypothesis, that a defect in cholesterol processing plays an important role in AMD.
In two later publications in the International Journal of Molecular Sciences (2018; 2019), Dr. Shu and his team investigated TSPO ligands, substances that can bind to TSPO and influence its activity. The chronic version of AMD involves changes in the choroid, the layer containing the vessels that supply the retina with blood. Dr. Shu’s group tested treatment of choroidal cells with TSPO ligands. These have shown anti-oxidative stress and anti-inflammatory properties, and the team’s study showed that TSPO ligands may offer promise for the treatment of AMD. Two of these TSPO ligands, Etifoxine and XBD-173, have already gone through clinical trials, demonstrating therapeutic effects in patients with anxiety. This means that, if treatment for AMD can be shown to be successful, these compounds can progress to clinical trials much faster. The group also showed that using genetic manipulation to suppress TSPO activity in RPE cells resulted in changes in various metabolic pathways, including increased oxidative stress. This study should contribute to a deeper understanding of AMD disease mechanisms.
Their findings demonstrate that TSPO is involved in cholesterol removal in the retinal pigment epithelium and that loss of TSPO causes abnormal build-up of cholesterol within cells; TSPO ligands can help improve cholesterol removal from RPE and choroidal cells and can suppress oxidative stress and inflammation. Their ongoing research is testing the protective effects of TSPO ligands in animal models and they are applying for funding to run clinical trials for TSPO ligands to treat AMD patients. They also plan to present their findings at the 35th Asia-Pacific Academy of Ophthalmology Congress, to be held in Xiamen, China, from April, 2020. “Given that people are living to increasingly older ages, macular degeneration of this type is a condition that will affect a growing proportion of the population, having a major detrimental effect on the quality of life of many individuals. Our efforts are focussed on developing potential strategies to treat AMD.” – Xinhua Shu (Reader, Department of Biological and Biomedical Sciences, Glasgow Caledonian University)
Dr. Aram Saeed and Dr. Graham Riley are Rosetrees Trust-funded researchers, based at the University of East Anglia, who are leading a project on investigating the development of a 3D printed implantable device for tendon regeneration and rupture repair. Dr. Eleanor Jones has been previously working on this project, and Miss Noelia Dominguez Falcon is the PhD candidate who is now working on this project. It is anticipated that this device could improve the clinical outcomes for patients suffering from tendon injuries.
This is what Aram had to say:
“Tendon injury is common and debilitating, and it is associated with long-term pain and ineffective healing, and is associated with high morbidity, pain, and long-term suffering for the patient. Once the damage has occurred, the repair process is slow and inefficient, resulting in mechanically, structurally, and functionally inferior tissue. Developing an implantable device that stimulates the body’s own repair system to produce de novo tissue through the use of factors such as cells, proteins, and tissue-specific biomaterials can lead to advanced new therapies to improve the clinical outcome and quality of life for patients”.
In previous Rosetrees Trust-funded research, the team successfully designed and developed a 3D printing technique to manufacture scaffold materials, and these had appropriate grooves to behave similarly to native tendon tissue. The research from this study has formed the basis for a continuation project which is currently funded by Rosetrees Trust.
In this continuation project, the team are further developing the basic scaffold materials into an implantable regenerative device, which is ultimately intended for clinical use. To achieve this outcome, the team are working to enhance existing protocols for the differentiation of adipose-derived stem cells to the tenogenic lineage in serum-free conditions. This along with a contribution to the understanding of tenogenic induction protocols has been recently published in Tissue Engineering Part C: Methods.
Dr. Athanasios Didangelos is a Rosetrees Trust-funded principal investigator at the University of Leicester, working in the Mayer IgA Nephropathy Laboratory led by Professor Jon Barratt. Their new publication in the Journal of Autoimmunity has identified a new urine marker in IgA Nephropathy (IgAN) known as PEBP4. The protein was found by deep-screening of the urinary proteome by shotgun mass-spectrometry proteomics.
Athanasios Didangelos and Scott
IgAN (a very common kidney disease) can lead to chronic kidney damage and renal failure. A substantial proportion of patients (~20%) end up needing expensive and burdensome dialysis as well as kidney transplants. It is therefore important to identify potential disease markers and/or soluble bioactive factors in IgAN to support early diagnosis and new treatment opportunities. Currently, there are no drugs that can treat IgAN and no biomarkers that can predict disease outcomes.
With the discovery of PEBP4, Dr. Didangelos and his team showed that its concentration is increased in serum and urine of IgAN patients. More importantly, the levels of the soluble protein in urine and serum appeared to positively correlate with the extent of kidney damage in IgAN patients.
The next steps of this research would require further investigation into the role of PEBP4 in kidney pathology. One particular area or interest, is the potential relationship of PEBP4 with B-cells (major disease effectors in IgAN) as well as its likely interplay with a key inflammatory factor named interferon gamma. Importantly, PEBP4 might be involved in inflammatory mechanisms in other diseased organs and tissues.
IgAN is a chronic and progressive disease that affects the kidneys of many thousands of patients in the UK and worldwide. Since there are no treatments for IgAN, these patients have to live for years with a condition that affects a major human organ as well as the devastating uncertainty of whether they will need dialysis or kidney transplantation in the future. I have met multiple IgAN patients and have understood the need to identify new treatment options and clinical prognostic tools for the disease. PEBP4 is a new soluble bioactive candidate that gives us the opportunity to investigate new treatment avenues, specifically targeting important inflammatory cell types (B-cells) and unexplored pathological pathways. Together with Professor Jon Barratt, our work at the Mayer IgA Nephropathy Laboratory, aims to identify new molecules and disease pathways that we can target in much needed future therapies.
Written by: Rebecca Downing and Dr. Athanasios Didangelos