Following spinal cord injury the extracellular matrix undergoes significant remodeling. Scar formation is associated with upregulation of molecules known to be inhibitory to neural plasticity and recovery of function, including chondroitin sulphate proteoglycans (CSPGs). Enzymatic removal of CSPG glycosaminoglycan chains by the bacterial protein Chondroitinase ABC (ChABC) renders the matrix more permissive to recovery, however this is curtailed by rapidly diminishing enzyme activity. We have previously demonstrated that gene therapy using a modified ChABC gene compatible with expression and secretion by mammalian host cells confers sustained and long-term delivery of ChABC to the injured spinal cord following a single administration. This treatment resulted in dramatic reduction in pathology and significant improvements in functional recovery following clinically relevant spinal contusion injury at both thoracic and cervical levels in adult rats. We now use novel immune-evasive vectors to enable regulatable gene therapy to exert greater control over ChABC expression, where ability to switch off delivery of ChABC greatly improves safety of the treatment. Using this system, doxycycline administration results in high expression of the ChABC gene and extensive functional enzymatic removal of inhibitory components present in the extracellular matrix. We also show this is accompanied by pro-reparative changes in inflammatory markers. We aim to utilise this system to manipulate timing and duration of ChABC delivery to adult rats which have received a clinically-relevant contusion injury to the cervical spinal cord and investigate its efficacy in promoting functional recovery. This represents both an experimental tool to optimise and control ChABC delivery to understand the role of timing in ChABC treatment, and a step towards clinical feasibility of ChABC gene therapy.
*E. R. BURNSIDE1, F. DE WINTER2, A. DIDANGELOS1, N. D. JAMES1, K. BARTUS1, E. M. MUIR3, J. VERHAAGEN2, E. J. BRADBURY1;
1King’s Col. London, London, United Kingdom; 2Netherlands Inst. for Neurosci., Amsterdam, Netherlands; 3Univ. of Cambridge, Cambridge, United Kingdom
E.R. Burnside: None. F. de Winter: None. A. Didangelos: None. N.D. James: None. K. Bartus: None. E.M. Muir: None. J. Verhaagen: None. E.J. Bradbury: None.