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Professor Tom Clutton-Brock, Director of the Medical Devices Testing and Evaluation Centre, Professor of Anaesthesia and Intensive Care Medicine at the University of Birmingham and Associate Medical Director at University Hospitals Birmingham NHS Foundation Trust, has been awarded an MBE for services to the NHS during the COVID-19 pandemic.

Professor Clutton-Brock and the MD-TEC team played a vital role in developing and testing ventilators in the Government’s Ventilator Challenge during the COVID-19 pandemic, helping to rapidly assess ventilator prototypes and advise on the approval process. Devices approved by the team are now in use at hospitals across several countries.

Professor Clutton-Brock said: “I am honoured to receive this award.  I have been interested in medical technologies and how to make them as safe and as usable as possible throughout my career. I have been continually supported by senior colleagues at UHB and UoB, for which I am also very grateful.  None of this work would have been possible without the hard work of the MD-TEC team, and of course the facility itself, located in the Institute of Translational Medicine.”

Professor Clutton-Brock, who is also the Chair of the NICE Interventional Procedures Advisory Committee and Clinical Director of the NIHR Trauma Management MedTech Cooperative, has previously been named one of the “100 most influential drivers of the health technology revolution”.

Tim Jones, Chief Innovation Officer at UHB, added: “On behalf of everyone at the Trust, I’d like to extend my congratulations to Tom, for this well-deserved recognition of his exceptional work that has and continues to have a huge impact on healthcare not only in the UK but also globally.”

The University of Birmingham has embarked on a new collaborative research project with the University of Cambridge, aiming to confirm whether selective P2X7 receptor blocker drugs can be repurposed to treat patients with secondary brain damage.

Funded by almost £1 million from the Medical Research Council, the project will be carried out in two phases over the next three years.

The leading cause of death and disability in those aged under 40, traumatic brain injury costs the UK economy an estimated £8 billion per year.  Mortality rates are high and many who survive suffer life-long disability, however there are currently no approved drugs available in the clinic to reduce the impact of such injuries on patients.

Principal Investigator Professor Nicholas Barnes, of the University of Birmingham’s School of Pharmacy, explains: “Whilst it would be difficult for a drug to reduce the consequences of the initial injury, the dead and dying brain tissue associated with the initial trauma can cause neuro-inflammation which spreads to surrounding brain tissue that may be damaged but not irreversibly.

“However, the added stress of neuro-inflammation to this adjacent brain tissue expands the volume of brain damage. This secondary, non-mechanical, brain damage begins over hours to days after the initial trauma and is hence may be considered amenable to potential pharmacological treatment with drugs.”

Previous research has shown that the P2X7 receptor – a protein in the body responsible for regulating inflammation – is involved in the physiological processes that stress brain tissue and can lead to brain cell death. The P2X7 receptor can evoke a chain of events that causes brain cells to secrete pro-inflammatory chemicals, adding to the stress upon brain cells following a traumatic brain injury.

Professor Barnes adds: “We are testing whether blocking the P2X7 receptor with a drug may put a brake on the processes contributing to stressing the brain cells and so help reduce the secondary brain damage subsequent to the traumatic injury.

“If successful, this will improve the clinical outcomes for patients following traumatic brain injury, allowing more patients to survive and reduce disability. If our prediction is correct, this would also provide a massive advance in the clinical management of patients with traumatic brain injury since there is no current effective drug treatment.”

First, the team will use small pieces of brain tissue from traumatic brain injury patients undergoing neurosurgery – this brain tissue comes away from the brain during standard neurosurgical techniques and its collection does not change the outcome for the patient.

In the laboratory, the team will carry out research using cells from the samples to identify the concentration of the drug required to be reached in the brain of patients to block the P2X7 receptor-mediated pro-inflammatory response of brain cells known as microglia. Following research in the laboratory, there will be further research to translate the laboratory work into a clinical trial.

The research team will also consist of Professor Tony Belli and Dr Valentina Di Pietro, both of the University of Birmingham, and Professor Peter Hutchinson, Mr Adel Helmy, and Dr Keri Carpenter, all of the University of Cambridge.

The research is also being supported by the National Institute for Health Research’s Surgical Reconstruction and Microbiology Research Centre, based at the Institute of Translational Medicine.

Scientists at the University of Birmingham have shown that a novel low molecular weight dextran-sulphate, ILB® could play a key role in treating open angle glaucoma (OAG), a neurodegenerative disease that affects over 70 million people worldwide and causes irreversible blindness.

OAG develops slowly over many years.  Excessive matrix deposition (fibrosis) within the eye’s main fluid drainage site can lead to increased intraocular pressure (IOP), resulting in damage to the optic nerve.¹

The research, reported in npj Regenerative Medicine, has shown that that ILB can normalise matrix deposition inside the eye and lower IOP in a pre-clinical model used to mimic these aspects of human glaucoma, paving the way for new anti-fibrotic therapies to be developed for the disease.

OAG is a complex disease and it has proved difficult to develop effective therapeutics to target the biochemical pathways involved.   Existing therapies mainly work by reducing fluid production in the eye, not the underlying causes, and even the newer therapies have shown limited success in the clinic.²

The Birmingham scientists focussed on an inflammatory pathway that is common to several diseases, and involves Transforming Growth Factor β (TGFβ), a signalling molecule that communicates between cells and orchestrates both inflammation and fibrosis.  TGFβ’s role in OAG is well known, with patients demonstrating higher levels in their aqueous humour and laboratory studies showing that artificially increasing TGFβ within the eye can lead to fibrosis^3,4.

The scientists found that ILB has multimodal actions across many genes that resolve inflammatory and fibrotic cellular processes.  When they progressed their work into a pre-clinical experimental model of glaucoma, they found that daily subcutaneous injections of ILB significantly (p<0.01) reduced extracellular matrix levels within the eye’s main drainage site, normalised the eye’s pressure and prevented degeneration of retinal neurons.  The research was conducted by Dr Lisa Hill, from the Institute of Clinical Sciences, and Dr Hannah Botfield, from the Institute of Inflammation and Ageing.  They commented:  “We are truly excited by these results, which show a way forward for a glaucoma treatment that can reverse the fibrotic process that causes the disease.”

Clinicians working in ophthalmology generally prefer local over systemically delivered therapeutics, as it is a safer route of administration that is more acceptable to patients.

Dr Hill is leading a project to formulate a topical alternative that will avoid the need for injection.  She is working closely on this with Mr Imran Masood, a consultant ophthalmic surgeon at Sandwell and West Birmingham NHS Trust and Professor Liam Grover, a biomaterials expert from the ITM-based Healthcare Technologies Institute, to assess the use of a novel shear thinning fluid gel for the resolution of glaucoma.

The shear thinning fluid gel was developed for use as eye drops that are retained for an extended period of time following administration, and patents have been filed for its use both alone, and in combination with other therapeutics.⁵  Previous studies have shown the fluid gel reduces corneal scarring when applied topically, and it is an effective carrier molecule for other therapeutics.⁶

ENDS

ILB® resolves inflammatory scarring and promotes functional tissue repair has been published in NPJ Regen Med.  DOI:  10.1038/s41536-020-00110-2

For further media information contact Ruth Ashton, Reputation and Communications Development Manager, University of Birmingham Enterprise, email: r.c.ashton@bham.ac.uk

For further information about the fluid gel patent, contact Helen Dunster, Business Development Manager, University of Birmingham Enterprise, email: H.Dunster@bham.ac.uk

About ILB®

ILB® is a unique and distinct LMW-DS formulation whose structure, formulation, synthesis and relevance to fibrotic diseases like glaucoma has been described in detail previously in two published patents (WO 2016/076780 and WO 2018/212708).  For this study, ILB® (batch number 3045586) was provided by Tikomed AB.

The study also benchmarked ILB® against an approved anti-fibrotic drug, pirfenidone, in cultured human cells, where it showed a unique anti-inflammatory response.

About University of Birmingham Enterprise

University of Birmingham Enterprise helps researchers turn their ideas into new services, products and enterprises that meet real-world needs.  We also support innovators and entrepreneurs with mentoring, advice, and training and manage the University’s Academic Consultancy Service.

References

1. Tektas, O. Y. & Lutjen-Drecoll, E. Structural changes of the trabecular meshwork in different kinds of glaucoma. Experimental Eye Research, 88(4), 769-75 (2009).
2. Friedman, S. L., Sheppard, D., Duffield, J. S. & Violette, S. Therapy for fibrotic diseases: Nearing the starting line. Science Translational Medicine 5(167), 167sr1-sr1 (2013).
3. Fuchshofer, R. & Tamm, E. R. The role of TGF-beta in the pathogenesis of primary open-angle glaucoma. Cell and Tissue Research, 347(1), 279-90 (2012).
4. Kim, K. S., Lee, B. H. & Kim, I. S. The measurement of fibronectin concentrations in human aqueous humor. Korean Journal of Ophthalmology, 6(1), 1-5 (1992).
5. Patent numbers: WO/2020/115510; WO/2020/115508; GB2008919.9
6. Hill et al.  Sustained release of decorin to the surface of the eye enables scarless corneal regeneration.  npj Regenerative Medicine. 3, 1-12 (2018).

A low cost and widely available drug could reduce deaths in traumatic brain injury patients by as much as 20 per cent depending on the severity of injury, according to a major study carried out at the ITM in collaboration with the University of Birmingham.

The research, published in The Lancet, showed that tranexamic acid (TXA), a drug that prevents bleeding into the brain by inhibiting blood clot breakdown, has the potential to save hundreds of thousands of lives.

The global randomised trial included more than 12,000 head injury patients who were given either intravenous tranexamic acid or a placebo.

It found that administration of TXA within three hours of injury reduced the number of deaths. This effect was greatest in patients with mild and moderate traumatic brain injury (20% reduction in deaths), while no clear benefit was seen in the most severely injured patients.

The trial found no evidence of adverse effects and there was no increase in disability in survivors when the drug was used. The trial was jointly funded by the Department for International Development (DFID), the Medical Research Council (MRC), the National Institute for Health Research (NIHR), (through the Department of Health and Social Care), and Wellcome. The early phase of the trial was funded was funded by The JP Moulton Charitable Foundation.

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide with an estimated 69 million new cases each year. The CRASH-3 (Clinical Randomisation of an Antifibrinolytic in Significant Head Injury) trial is one of the largest clinical trials ever conducted into head injury. Patients were recruited from 175 hospitals across 29 countries.

Bleeding in or around the brain due to tearing of blood vessels is a common complication of TBI and can lead to brain compression and death. Although patients with very severe head injuries are unlikely to benefit from tranexamic acid treatment because they often have extensive brain bleeding prior to hospital admission and treatment, the study found a substantial benefit in patients with less severe injuries who comprise the majority (over 90%) of TBI cases.

Co-investigator for trial Professor Tony Belli, of the University of Birmingham’s Institute of Inflammation and Ageing, said: “This is a landmark study. After decades of research and many unsuccessful attempts, this is the first ever clinical trial to show that a drug can reduce mortality after traumatic brain injury.

“Not only do we think this could save hundreds of thousands of lives worldwide, but it will no doubt renew the enthusiasm for drug discovery research for this devastating condition.”

Ian Roberts, Professor of Clinical Trials at the London School of Hygiene & Tropical Medicine, who co-led the study, added: “We already know that rapid administration of tranexamic acid can save lives in patients with life threatening bleeding in the chest or abdomen such as we often see in victims of traffic crashes, shootings or stabbings.

“This hugely exciting new result shows that early treatment with TXA also cuts deaths from head injury. It’s an important breakthrough and the first neuroprotective drug for patients with head injury.

“Traumatic brain injury can happen to anyone at any time, whether it’s through an incident like a car crash or simply falling down the stairs.

“We believe that if our findings are widely implemented they will boost the chances of people surviving head injuries in both high income and low income countries around the world.”

Because TXA prevents bleeds from getting worse, but cannot undo damage already done, early treatment is critical. The trial data showed a 10% reduction in treatment effectiveness for every 20-minute delay, suggesting that patients should be treated with TXA as soon as possible after head injury.

Dr Ben Bloom, Consultant in Emergency Medicine at Barts Health NHS Trust, the UK’s largest recruiter into the trial with more than 500 patients enrolled, said: “Treating traumatic brain injury is extremely challenging with very few treatment options available for patients. Thanks to these latest results, which are applicable to patients with head injuries of any cause and of all demographics, clinicians now have a potentially powerful new treatment available to them.”

The most common causes of TBI worldwide are road traffic crashes, which predominantly affect young adults, or falls, which are a major problem in older adults, and the incidence is increasing. In both cases, patients can experience permanent disability or death. Representatives from the charity that supports roach crash victims in the UK, Roadpeace, were involved in the design of the trial.

Amy Aeron-Thomas, Justice and Advocacy Manager from Roadpeace and co-author on the paper said: “It’s always better to prevent road crashes in the first place, but these results show that if a crash can’t be prevented, death can still be avoided.

“Given the time to treatment implications, it’s more important than ever that the post-crash response is as efficient as possible.”

CRASH-3 follows successful previous research involving 20,000 trauma patients, which showed that TXA reduced deaths due to bleeding outside of the skull by almost a third if given within three hours. Based on those trial results, tranexamic acid was included in guidelines for the pre-hospital care of trauma patients. However, patients with isolated traumatic brain injury were specifically excluded.

The authors noted some limitations of the trial, including wide confidence intervals despite the large trial size, and the fact that more patients with un-survivable head injuries were included in the trial than anticipated, which diluted the treatment effect.