Background: Spinal cord injuries have devastating consequences because injured CNS axons do not regenerate. This is for two key reasons: an inhibitory scar environment and a limited growth ability (extrinsic and intrinsic factors). The Bradbury lab have pioneered a gene therapy to overcome the scar (chondroitinase), whilst The Eva lab use gene therapy to increase axon growth capacity. One of the genes used is “Protrudin”, a powerful molecule that moves crucial machinery into the injured axon.
Translation: Protrudin is particularly exciting because it works in an unexpected way, meaning that our current studies are identifying ways of improving its actions, enabling optimisation of gene therapy candidates for stimulating regeneration after spinal cord injury.
Aims: This project aims to produce combined gene therapies for stimulating functional regeneration in the injured spinal cord by combining intrinsic growth stimulators with the extrinsic modifier chondroitinase. It will uncover new axon biology whilst identifying clinically relevant therapies for spinal cord repair.
Techniques: Ranging from neuronal cell biology through to translational biotechnology and animal models of CNS injury. Cutting-edge live imaging of cultured neurons, fluorescent microscopy, cell biology, design of gene therapy candidates, and testing of these using neuronal injury models and pre-clinical models of spinal cord injury.
Objectives: Year one will focus on the neuronal biology of Protrudin and its molecular partners as well as axonal biology, focusing on axon organelles. This will identify candidates for enhancing gene therapy vectors. Year two will use the vectors generated in year one, testing effects on axon growth and regeneration in neuronal cell models of injury, and measuring aspects of axonal cell biology during enhanced regeneration. Years three and four will test the optimised gene therapy candidate in a pre-clinical model of spinal cord injury, measuring the extent of regeneration and functional recovery after single and combination therapies.
SpineRevive: Targeted gene therapies for spinal cord regeneration.
Representative Publications
Protrudin functions from the endoplasmic reticulum to support axon regeneration in the adult CNS. Petrova V., Pearson C. S., Ching J., Tribble J. R., Solano A. G., Yang, Y., Love F.M., Watt R.J., Reid E., Williams P. A., Geller H.M., Eva R. & Fawcett J.W. 2020. Nature Communications. doi.org/10.1038/s41467-020-19436-y.
Joint Senior Author. PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS. B. Nieuwenhuis, A. C. Barber, R. S. Evans, C. S. Pearson, J. Fuchs, A. R. MacQueen, S. van Erp, B. Haenzi, L. A. Hulshof, A. Osborne, R. Conceicao, S. S. Deshpande, J. Cave, C. ffrench-Constant, P. D. Smith, K. Okkenhaug, B. J. Eickholt, K. R. Martin, J. W. Fawcett, R. Eva. EMBO Molecular Medicine. 2020. doi.org/10.15252/emmm.201911674.
Selective Rab11 transport and the intrinsic regenerative ability of CNS axons. Koseki, H., Donegá, M., Lam, B.Y.H., Petrova, V., Yeo, G.S.H., Kwok, J.C.F., van Erp, S., ffrench-Constant, C., Eva, R., Fawcett, J.W. eLife. 2017, doi: 10.7554/eLife.26956.
Joint corresponding author. Chondroitin sulfate proteoglycans prevent immune cell phenotypic conversion and inflammation resolution via TLR4 in rodent models of spinal cord injury. Francos-Quijorna I, Sánchez-Petidier M, Burnside ER, Badea SR, Torres-Espin A, Marshall L, de Winter F, Verhaagen J, Moreno-Manzano V, Bradbury EJ. Nature Communications. 2022 May 25;13(1):2933. https://doi.org/10.1038/s41467-022-30467-5
Immune-evasive gene switch enables regulated delivery of chondroitinase after spinal cord injury. Burnside ER, De Winter F, Didangelos A, James ND, Andreica EC, Layard-Horsfall H, Muir EM, Verhaagen J, Bradbury EJ. Brain. 2018 Aug 1;141(8):2362-2381. https://doi.org/10.1093/brain/awy158 Moving beyond the glial scar for spinal cord repair. Bradbury EJ, Burnside ER Nature Communications. 2019 Aug 28;10(1):3879 10:3879. https://doi.org/10.1038/s41467-019-11707-7