Combinatorial testing of transcriptional modification and chondroitinase treatment to promote axon regeneration and functional recovery after spinal cord injury

Society for Neuroscience Chicago 2015

Poster 226. Spinal Cord Injury: Restorative Strategies Location: Hall A Time: Sunday, October 18, 2015, 1:00 PM – 5:00 PM Program#/Poster#: 226.25/H35
Topic: C.10. Trauma
Support: NIH Grant NS083983-01 The International Spinal Research Trust

Title: Combinatorial testing of transcriptional modification and chondroitinase treatment to promote axon regeneration and functional recovery after spinal cord injury

Authors: *Z. WANG, K. WINSOR, E. BALLE, P. POWERS, N. KRUEGER, M. BLACKMORE; Dept. of Biomed. Sci., Marquette Univ., Milwaukee, WI

Abstract: Axon regeneration in the central nervous system (CNS) is prevented by extracellular inhibitory cues, as well as a failure on the part of many injured CNS neurons to activate transcriptional programs needed to sustain axon growth. We have previously identified two transcription factors, KLF7 and Sox11, which enhance regenerative axon growth when overexpressed in adult corticospinal tract (CST) neurons. Here we explore the hypothesis that combining these transcriptional interventions with chondroitinase, an enzyme that degrades growth-inhibitory chondroitin sulfate proteoglycans, may lead to additional gains in axon regeneration and/or behavioral recovery. We created a lentiviral vector to drive expression of chondroitinase in host cells (Lenti-Chase) and confirmed that Lenti-Chase injections caused CSPG degradation in the injured spinal cord using immunohistochemistry with 2B6, and antiCSPG stub antibody. In one set of experiments, a thoracic crush experiment was performed in adult mice, and CST neuronal cell bodies were treated with transcriptional active KLF7 (AAV8VP16-KLF7) while Lenti-Chase was delivered to the site of spinal injury. Compared to control viral treatments, KLF7-treated axons showed enhanced proximity to the proximal side of the injury, an effect that appeared to be elevated in the presence of Lenti-Chase. In contrast to previous results using partial spinal injury, however, KLF7-stimulated axons were not observed to regenerate distal to the complete crush injury. In a second experiment, animals were challenged with a cervical hemisection, and AAV-Sox11 treatment of CST cell bodies was combined with spinal lenti-Chase. Consistent with our previous results, Sox11 significantly enhanced CST axon growth distal to the injury site. Growth was not further increased by application of Lenti-Chase. Animals did, however, show a trend toward behavioral improvement when Sox11 and Chondroitinase were combined. Replicating this finding, and further combining these treatments with rehabilitative training, are areas of ongoing research

Disclosures: Z. Wang: None. K. Winsor: None. E. Balle: None. P. Powers: None. N. Krueger: None. M. Blackmore: None.

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