Gene delivery of chondroitinase ABC promotes functional repair following spinal cord injury

There is new hope for the use of viral delivery of ch’ase (Chondroitinase ABC) as a way to treat a much broader area of the spinal cord and for more (LENGTHY TIME PERIODS) (LINK) Because contusive lesions are so large simple injection of the enzyme after such injuries has not been very successful. Things are changing now and here is an abstract from the Bradbury lab in London at King’s College to explain this new strategy. Dr. Jerry Silver is collaborating and using this viral delivery strategy in his lab at Case Western Reserve University in Cleveland as well as his lab’s new peptide to produce long term, widespread effects.
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Program#/Poster#: 270.07/EE19
Location: Hall F-J Neuroscience 2012, SfN’s 42nd annual meeting, is scheduled for Oct. 13 -17 in New Orleans at the Ernest N. Morial Convention Center.
Presentation time: Sunday, Oct 14, 2012, 3:00 PM – 4:00 PM
Authors: *N. D. JAMES1, K. BARTUS1, J. SHEA1, K. BOSCH1, J. H. ROGERS2, S. B. MCMAHON1, B. L. SCHEIDER3, E. M. MUIR2, E. J. BRADBURY1;
1King’s Col. London, London, United Kingdom; 2Univ. of Cambridge, Cambridge, United Kingdom; 3Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Abstract: Spinal cord extracellular matrix is densely packed with growth inhibitory chondroitin sulphate proteoglycans (CSPGs), which become more abundant after injury. Thus, matrix modification has become a leading experimental strategy for promoting repair following spinal cord injury. Despite the beneficial effects that have been achieved by digesting CSPGs with the bacterial enzyme chondroitinase ABC (ChABC), the potential for achieving long term efficacy in traumatic injuries that mimic a human spinal cord injury has not yet been realised. Gene therapy offers a route to achieving stable continuous delivery of ChABC and therefore, here we deliver genetically modified ChABC via a lentiviral vector (LV-ChABC) to the adult rat spinal cord and assess the efficacy of chronic gene delivery using a spinal contusion injury model. Contusion injury represents the most common form of spinal cord injury in humans and, therefore, provides a clinically relevant tool for assessing the efficacy of potential therapeutic interventions. Adult rats received a moderate severity thoracic (T10) contusion injury and LV-ChABC or a control LV-GFP was immediately injected rostral and caudal to the injury site. We demonstrate prolonged and widespread CSPG degradation with LV-ChABC and, using both behavioural and electrophysiological outcome measures, we show improved function in animals treated with LV-ChABC. We saw a dramatic increase in spinal conduction through the injury site as well as a significant improvement in performance on the horizontal ladder test. In addition we will determine if the early functional improvements observed using the horizontal ladder test correlate with changes in spinal conduction at early time points. In order to enhance the potential clinical applications of this study we are now assessing the effects of LV-ChABC in a moderate severity cervical (C5) contusion injury. Approximately 50% of all human spinal cord injuries occur at the cervical level making this injury model of particular clinical relevance as well as allowing us to assess a number of additional functional outcomes such as forelimb grip-strength, sensory and motor function during sticky-tape removal, and proprioception using the inclined plane. Thus, we demonstrate the potential advantages of gene delivery of ChABC for achieving sustained and widespread CSPG degradation and that this is associated with functional improvements following contusion injury.

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