Combining Constitutively Active Rheb Expression and Chondroitinase Promotes Functional Axonal Regeneration after Cervical Spinal Cord Injury

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Abstract

After spinal cord injury (SCI), severed axons in the adult mammalian CNS are unable to mount a robust regenerative response. In addition, the glial scar at the lesion site further restricts the regenerative potential of axons. We hypothesized that a combinatorial approach coincidentally targeting these obstacles would promote axonal regeneration. We combined (1) transplantation of a growth-permissive peripheral nerve graft (PNG) into an incomplete, cervical lesion cavity; (2) transduction of neurons rostral to the SCI site to express constitutively active Rheb (caRheb; a Ras homolog enriched in brain), a GTPase that directly activates the growth-promoting pathway mammalian target of rapamycin (mTOR) via AAV-caRheb injection; and (3) digestion of growth-inhibitory chondroitin sulfate proteoglycans within the glial scar at the distal PNG interface using the bacterial enzyme chondroitinase ABC (ChABC). We found that expressing caRheb in neurons post-SCI results in modestly yet significantly more axons regenerating across a ChABC-treated distal graft interface into caudal spinal cord than either treatment alone. Excitingly, we found that caRheb+ChABC treatment significantly potentiates the formation of synapses in the host spinal cord and improves the animals’ ability to use the affected forelimb. Thus, this combination strategy enhances functional axonal regeneration following a cervical SCI. After spinal cord injury, extrinsic and intrinsic factors limit axon regeneration. Wu et al. concurrently addressed both by combining neuronal expression of a constitutively active version of the GTPase Rheb with chondroitinase modulation of the growth-inhibitory glial scar. This resulted in improved axon regeneration, enhanced synapse formation, and improved functional recovery.

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Wu, D., Klaw, M. C., Connors, T., Kholodilov, N., Burke, R. E., Côté, M. P., & Tom, V. J. (2017). Combining Constitutively Active Rheb Expression and Chondroitinase Promotes Functional Axonal Regeneration after Cervical Spinal Cord Injury. Molecular Therapy, 25(12), 2715–2726. https://doi.org/10.1016/j.ymthe.2017.08.011

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