'Ischemic' spinal cord injuries occur when blood flow to the spinal cord is restricted. The consequences can be devastating - including paralysis of the legs, incontinence, impotence and increased risk of death.
In this project, Dr Philippa Warren and colleagues set out to answer key questions about the way that these injuries develop. They will use their findings to work out a treatment strategy that will then be tested in their experimental model.
Following rigorous assessment as part of our competitive grant round, this impactful and well-designed project was recommended for its strong potential to advance our understanding of ischemic spinal cord injury. Led by early career researcher Dr Philippa Warren, the collaborative team is well-placed to take forward this important work for the benefit of patients affected by this devastating condition.
One in five spinal injury patients acquire their injury through a non-traumatic cause.
‘Ischemic’ spinal cord injuries are caused by restricted blood flow to the spinal cord. This decrease in blood flow means that cells are starved of blood and oxygen, leading to cell death. If blood flow to the spinal cord is subsequently restored, the toxic molecules that are generated during cell death flood to uninjured parts of the cord. This compounds the initial damage, causing cells in these regions to die and destroying the connections from the brain to the lower limbs.
These injuries most commonly arise as a complication following surgery to repair an aortic aneurysm, and can result in paralysis of the legs, incontinence, impotence, and increased risk of death.
There is no effective method to treat the paralysis caused by ischemic spinal cord injury.
Read more: Brain and spinal cord injury
It is known that ischemic spinal cord injuries cause substantial degrees of cell death, and that this can be reduced by applying means to protect the nervous system. However, to develop an effective treatment that can protect the nervous system in this way, we need to know the exact molecules and pathways to target in human patients.
Dr Warren and team are setting out to answer three key questions:
They will firstly characterise how experimental ischemic injury to the spinal cord changes the composition and integrity of the cord over time. This will be compared to the development of injuries formed following a hit to the spinal cord (which are more commonly studied).
This will enable them to determine whether these different types of injuries affect the spinal cord in the same way, and the best time to apply a treatment to get the most beneficial effects. They will examine data from human patients with ischemic spinal cord injuries, showing their molecular changes in the spinal cord, to discover new and clinically significant treatment targets.
With this information they will design a treatment strategy that can be applied at the optimal time and place after injury, and will target molecules known to be important in injury development.
Finally, they will test their treatment strategy experimentally to determine its effect on restoring spinal cord structure, organisation, neuronal function, muscle activity, and locomotor function.
The use of rats is essential in this research, as the types of questions being asked cannot be addressed in any other way – there are no cellular, molecular or computer models that accurately replicate the complexity of human spinal cord injury. This aspect of the work was carefully reviewed, and is subject to tight regulation by the Home Office. The team will take the utmost care that the rats don’t experience pain or discomfort, and their procedures will be continuously monitored. They reduce animal numbers by sharing data and taking multiple recordings from the same animal and refine their protocol and experiments to make sure that the data is translatable to humans.
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There is currently no treatment to reverse the damage caused by ischemic spinal cord injury, and no prospect of recovery of function for affected patients.
In this important work, Dr Warren and team will advance our understanding of this devastating injury, delineating the underlying processes and revealing the changes that the injury causes to the spinal cord at a molecular level. This will facilitate the identification and development of new, clinically relevant treatment strategies, which will then be tested in their animal model.
“About 20% of all spinal patients acquire their spinal cord injury through a non-traumatic (non-mechanical) cause, for example as the result of a surgical procedure as is the basis of this project. These spinal cord injuries are somewhat overlooked and relatively under-researched world wide compared to the more obvious traumatic causes of spinal cord injury. It is exciting to see a project focusing on ischemic spinal cord injury and the findings in this context may be have a much wider application in spinal cord injury repair and in ischemic CNS injury.” External reviewer
Based at the Wolfson Centre for Age-Related Diseases, an interdisciplinary and world-leading neuroscience department at King’s College London, Dr Philippa Warren, is an expert on motor effects following spinal cord injury, and how injuries change over time. She is experienced in the generation of models that are relatable to the human condition, and has worked previously with the experimental model of ischemic spinal cord injury that will be used in this project.
She is working with Professor Elizabeth Bradbury, a leading authority on the use of drug treatments to stimulate recovery after spinal cord injury. Her team is developing advanced therapeutics for use in the clinic and will be key to the development of the treatment strategy.
Also contributing to the project is Professor Bijan Modarai, Chair of Vascular Surgery at Guys and St Thomas' NHS Trust, who treats clinical patients with vascular disorders including ischemic spinal cord injury. He will advise on the experimental models and data while providing access to anonymised patient data.
The combined expertise of this team will ensure project feasibility and success, and will aid clinical translation.
Acquired brain and spinal cord injury (including stroke) is one of our current research priorities, reflecting the large unmet need in this area. Our aim is to fund research to advance understanding of how to promote repair of the brain and spinal cord following injury.
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