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Prof.Liz Bradbury at Kings College London

CHASE-IT

Chondroitinase ABC for Spinal Injury Therapy

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.

Chondroitinase is able to modify the scar tissue which developes after a spinal cord injury and promote rewiring of the nervous system.

Scientific leads:
Professor Elizabeth Bradbury, King’s College London
Dr Elizabeth Muir, University of Cambridge
Professor Joost Verhaagen, Netherlands Institute for Neuroscience
Professor Rafael Yáñez-Muñoz, Royal Holloway University of London

The motivation to develop the CHASE-IT consortium came from the remarkable finding that chondroitinase enzyme delivered via gene therapy, leads to far better neurological outcomes than direct injection of the enzyme, particularly in contusion injuries. This was only made possible by the molecular re-engineering of chondroitinase, developed 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.

The teams are researching toxicity reduction, the chance of tumour formation and containing the treatment to the target tissue.

Studies showed that delivering chondroitinase by gene therapy gave far better results than direct injection of the bacterial protein.  Encouraged by this, the CHASE-IT consortium is now focussed on optimising the gene therapy approach to make it clinically acceptable. Intially this 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 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 its 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.

Next translational steps

The next stage of development, has four key elements 

1. Demonstrate that 'on-off' chondroitinase gene therapy works in different types of injury

2. Transfer the inducible gene therapy machinery, developed in a lentiviral vector (LV), to a more clinically-acceptable Adeno-associated viral (AAV) vector

3. Eliminate any background expression of chondroitinase when system in the ‘off’ state

4. Confirm chondroitinase-AAV retains comparable efficacy as chondroitinase-LV

History of chondroitinase
Swen in the pub

It's the simple things I miss, making my own cup of tea, cooking my own food - the way I want it, holding the knife and fork myself.

Swen on the things that matter to him

The Facts

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3

people every day are told they will never walk again
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50,000

People in the UK and Ireland are living with paralysis caused by spinal cord injury
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2.5 million

people worldwide live with paralysis caused by spinal cord injury

Research is possible but we need you

Help us fund the next stage of research in this potentially life-changing treatment.