Chondroitinase gene therapy improves upper limb function following cervical contusion injury

Nicholas D James,Jessie Shea,Elizabeth M Muir,Joost Verhaagen,Bernard L Schneider,Elizabeth J Bradbury

doi:10.1016/j.expneurol.2015.05.022

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.

Highlights

Spinal cord injury (SCI) is a devastating condition, leading to varying degrees of motor, sensory and autonomic deficits and for which there is currently no adequate treatment
Animals treated with LV-chondroitinase ABC (ChABC) displayed significantly improved functional recovery on the horizontal ladder compared to all other treatment groups at all post-injury time points beyond 3 weeks (p b 0.01; two-way RM ANOVA, Bonferroni post-hoc), such that by 10 weeks post-injury LV-ChABC treated animals were making 33.3 ±
Chondroitinase gene therapy leads to improved long distance axonal conduction through a cervical contusion site

Summary

Introduction

Spinal cord injury (SCI) is a devastating condition, leading to varying degrees of motor, sensory and autonomic deficits and for which there is currently no adequate treatment. Following the initial trauma to the spinal cord, complex pathological interactions lead to a cascade of secondary damage which results in the establishment of a peri-lesional area which potently inhibits axonal growth and spinal repair (Hagg and Oudega, 2006). This is one of the main reasons for the lack of functional recovery following SCI. Chondroitin sulphate proteoglycans (CSPGs) are known to contribute to the intensely inhibitory environment present at the lesion site, where they are heavily upregulated following SCI, preventing effective regeneration or repair of the damaged spinal cord (Cregg et al, 2014). The use of the bacterial enzyme chondroitinase ABC (ChABC) to breakdown CSPGs has repeatedly been shown to have beneficial effects on spinal repair following traumatic injury by numerous different research groups and in a number of different animal species and injury models (Ramer et al, 2014; Garcia-Alias et al, 2009; Bradbury et al, 2002; Alilain et al, 2011)

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Conclusion