Elizabeth Bradbury, King's College London, London, UK

Regulated chondroitinase gene therapy for restoring upper limb and hand function

Funded in: 2020, 2021, 2022

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Problem: Chondroitinase is a promising enzyme therapy, but there are a number of hurdles to translate it into a therapy
Target: Development of a prototype regulatable chondroitinase therapy
Goal: Advance the clinical translation of a novel chondroitinase gene therapy

Chondroitinase is a promising enzyme that enables as a part of a new therapy new growth and rewiring of spinal nerve cells when delivered to the injured spinal cord. Although many pre-clinical experimental studies have shown positive effects of chondroitinase, there are a number of hurdles to translating this therapy into a safe and effective treatment for humans. In this twin project with the research group of Joost Verhaagen (Netherlands Institute for Neuroscience) the scientists propose to advance the clinical translation of a novel chondroitinase gene therapy.
With a gene therapy approach, the chondroitinase gene can be packaged into a “viral vector”. Viral vectors are used as a carrier to deliver a gene into a nerve cell, rather like a parcel delivery. The viral vector is injected into the spinal cord and inserts the chondroitinase DNA into spinal cord cells. The cells can then produce and release the enzyme directly into spinal cord tissue, very stably over long periods of time.
To add a safety element, the Verhaagen group have developed a gene switch which enables precise control of gene delivery. The chondroitinase gene can be switched on and off by administering an antibiotic called doxycycline which is commonly used in the clinic (the gene is “on” when doxycycline is given orally and off when doxycycline is withdrawn). Here the researchers aim to develop and test the performance of these “regulatable chondroitinase vectors”. The scientists will assess new “AAV vectors” that will be developed in the Verhaagen lab (AAV vectors have an impressive clinical safety profile) and our current gold-standard vectors. They will determine whether these therapies are effective in chronic injuries and how best to combine regulatable chondroitinase gene therapy with a rehabilitative training regime to restore hand function in rats with chronic contusion injuries at the cervical level (which affects arm and hand function). Importantly, the researchers will carry out “immunogenicity” studies to find out how the host immune system responds to this therapy. The combined results obtained in the Bradbury and Verhaagen laboratories should lead to the development of a prototype regulatable chondroitinase AAV vector that can be rapidly translated to the clinic.