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Brain Advance Access published online on September 2, 2008
Brain, doi:10.1093/brain/awn206
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© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Deoxyribozyme-mediated knockdown of xylosyltransferase-1 mRNA promotes axon growth in the adult rat spinal cord

Andres Hurtado1,3, Heidrun Podinin2,4, Martin Oudega1,3 and Barbara Grimpe2,4

1International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, 2The Miami Project to Cure Paralysis, 3Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD and 4Department of Neurological Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA

Correspondence to: Barbara Grimpe, PhD, The Miami Project to Cure Paralysis, University of Miami Leonard M. Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA E-mail: b.grimpe{at}miami.edu

In the injured spinal cord, proteoglycans (PGs) within scar tissue obstruct axon growth through their glycosaminoglycan (GAG)-side chains. The formation of GAG-side chains (glycosylation) is catalysed by xylosyltransferase-1 (XT-1). Here, we knocked down XT-1 mRNA using a tailored deoxyribozyme (DNAXTas) and hypothesized that this would decrease the amount of glycosylated PGs and, consequently, promote axon growth in the adult rat spinal cord. A continuous 2-week delivery of DNAXTas near the rostral border of a peripheral nerve graft bridging the transected dorsal columns in the thoracic spinal cord resulted in an 81% decrease in XT-1 mRNA, an average of 1.4-fold reduction in GAG-side chains of chondroitin sulphate or heparan sulphate–PGs and 2.2-fold reduction in neurocan and brevican core proteins in scar tissue. Additionally, compared to control deoxyribozyme, the DNAXTas treatment resulted in a 9-fold increase in length and a 4-fold increase in density of ascending axons growing through the nerve graft and scar tissue present at the rostral spinal cord. Together our data showed that treatment with a deoxyribozyme against XT-1 mRNA decreased the amount of glycosylated PGs and promoted axon growth through scar tissue in the injured spinal cord. The deoxyribozyme approach may become a contributing factor in spinal cord repair strategies.

Key Words: scar; neurocan; brevican; XT; DNA enzyme

Abbreviations: CS, chondroitin sulfate; CTB, cholera toxin B subunit; DNA, deoxyribonucleic acid; DS, dermatan sulphate; GAG, glycosaminoglycan; GFAP, glial fibrillary acidic protein; HS, heparin sulphate; mRNA, messenger ribonucleic acid; PB, phosphate buffer; PBS, phosphate-buffered saline; PG, proteoglycan; XT-1, xylosyltransferase-1

Received February 6, 2008. Revised August 5, 2008. Accepted August 6, 2008.


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