title: Chondroitinase gene therapy improves upper limb function following cervical contusion injury.
abstract: Chondroitin sulphate proteoglycans (CSPGs) are known to be important contributors to the intensely inhibitory environment that prevents tissue repair and regeneration following spinal cord injury. The bacterial enzyme chondroitinase ABC (ChABC) degrades these inhibitory molecules and has repeatedly been shown to promote functional recovery in a number of spinal cord injury models. However, when used to treat more traumatic and clinically relevant spinal contusion injuries, findings with the ChABC enzyme have been inconsistent. We recently demonstrated that delivery of mammalian-compatible ChABC via gene therapy led to sustained and widespread digestion of CSPGs, resulting in significant functional repair of a moderate thoracic contusion injury in adult rats. Here we demonstrate that chondroitinase gene therapy significantly enhances upper limb function following cervical contusion injury, with improved forelimb ladder performance and grip strength as well as increased spinal conduction through the injury site and reduced lesion pathology. This is an important addition to our previous findings as improving upper limb function is a top priority for spinal injured patients. Additionally great importance is placed on replication in the spinal cord injury field. That chondroitinase gene therapy has now been shown to be efficacious in contusion models at either thoracic or cervical level is an important step in the further development of this promising therapeutic strategy towards the clinic.
authors.affiliation: King's College London, Regeneration Group, The Wolfson Centre for Age-Related Diseases, Guy's Campus, London Bridge, London SE1 1UL, UK.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: James
authors.affiliation: King's College London, Regeneration Group, The Wolfson Centre for Age-Related Diseases, Guy's Campus, London Bridge, London SE1 1UL, UK.
authors.forename: Jessie
authors.initials: J
authors.lastname: Shea
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Muir
authors.affiliation: Laboratory for Neuroregeneration, Netherlands Institute for Neuroscience, 1105BA Amsterdam, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Verhaagen
authors.affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Schneider
authors.affiliation: King's College London, Regeneration Group, The Wolfson Centre for Age-Related Diseases, Guy's Campus, London Bridge, London SE1 1UL, UK. Electronic address: elizabeth.bradbury@kcl.ac.uk.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Bradbury
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D019765:Chondroitin ABC Lyase / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005552:Forelimb / Q000502:physiology*; D020233:Gait Disorders, Neurologic / Q000209:etiology / Q000628:therapy; D015316:Genetic Therapy / Q000379:methods*; D016086:Lentivirus / Q000235:genetics; D008297:Male; D053580:Muscle Strength / Q000502:physiology; D009431:Neural Conduction / Q000502:physiology; D011596:Psychomotor Disorders / Q000209:etiology / Q000628:therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000235:genetics / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000150:complications / Q000473:pathology / Q000628:therapy*
chemical_list: D019765:Chondroitin ABC Lyase
keywords: Cervical contusion; Chondroitinase ABC; Gene therapy; Spinal cord injury