Clinical translation of chondroitinase as a potential therapy for spinal cord injury – CHASE-IT
Prof Elizabeth Bradbury, King’s College London
Dr Elizabeth Muir, University of Cambridge
Prof Joost Verhaagen, Netherlands Institute for Neuroscience
Dr Rafael Yáñez-Muñoz, Royal Holloway University of London
The aim of the CHASE-IT project is to develop an effective therapy for spinal cord injury using the neuroplasticity enhancing properties of the bacterial enzyme chondroitinase.
After a spinal cord injury, a scar develops which blocks the way for re-growing nerves which might otherwise be capable of making useful new connections to restore movement and function. Chondroitinase is able to modify the scar tissue and promote rewiring of the nervous system.
The motivation to develop the CHASE-IT consortium came from remarkable findings that chondroitinase delivered as a gene rather than directly as a protein leads to far better neurological outcomes, particularly in contusion injuries. This was only made possible by the molecular re-engineering of the chondroitinase gene carried out by Dr Liz Muir and colleagues at University of Cambridge who created a version of chondroitinase that could be expressed by human cells.
The challenges of developing a gene therapy treatment for spinal cord injury are considerable.
Specifically, the teams are working to reduce toxicity, remove the chance of tumour formation and contain the treatment to the target tissue.
They have chosen to focus on two different delivery systems to transport chondroitinase to the injury site in animal models of spinal cord injury. Both delivery systems are similar in concept and work in broadly the same way by making use of a virus as a vehicle to carry a therapeutic gene into cells which then go on to produce the therapeutic protein chondroitinase.
Recent studies have shown that delivering chondroitinase by gene therapy gives far better results than direct injection of the bacterial protein. Encouraged by this, the CHASE-IT consortium was established to work on optimizing the gene therapy approach to make it clinically acceptable. Primarily this has meant the development of an effective way to turn the treatment ‘on’ and ‘off’ when used in patients as this is a key safety issue.
In November 2016 the CHASE-IT consortium team at King’s College London identified a suitable antibiotic, called doxycycline that does this. They found the different levels between the ‘on’ and ‘off’ states with this drug were extremely high, which means they could see the enzyme working and not working. This bodes well for safe clinical application as it means it’s actions can be monitored and managed effectively.
Just as exciting, they also found that long-term treatment showed, for the first time, very significant improvements in forelimb and paw function in a contusion injury. These functions are under the control of the corticospinal tract (CST) which is known to be particularly poor in its regenerative response. The CST is also known to be particularly important for motor function in humans, allowing movement of the body.
Formal safety and toxicology studies are now needed to determine and demonstrate the safety profile. We now require funding to allow us to perform these studies before an application can be made for clinical trial.
This progress has only been possible because of our amazing supporters, who have believed in the research and generously supported it, enabling us to discover more about this very important enzyme and its effects on nerve regeneration.
Other Translational projects
Olfactory ensheathing cells (OECs)
Olfactory ensheathing cells are cells found in the nose that can provide new cellular pathways down which nerves can grow to make new connections. We are currently completing the contract for this third project led by David Choi at the UCL Institute of Neurology. This project will isolate and culture the human form of olfactory ensheathing cells, which have already proved effective in enabling nerve re-growth after spinal cord injury in animals.
An early intervention treatment using poli-unsaturated fatty acids (PUFAs) which can be applied immediately after a spinal injury to limit damage. At Queen Mary, University of London, Professor Adina Michael-Titus reports that the PUFA solution which is being developed for clinical use appears to be stable and is well tolerated, so it seems feasible to concentrate and stabilise these fatty acids for use in emergency situations.