Combining Constitutively Active Rheb Expression and Chondroitinase Promotes Functional Axonal Regeneration after Cervical Spinal Cord Injury.
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.
['Wu|Di|D|', 'Klaw|Michelle C|MC|', 'Connors|Theresa|T|', 'Kholodilov|Nikolai|N|', 'Burke|Robert E|RE|', 'Côté|Marie-Pascale|MP|', 'Tom|Veronica J|VJ|']
D000256:Adenoviridae D000818:Animals D001369:Axons D001522:Behavior, Animal D001921:Brain D019765:Chondroitin ABC Lyase D004195:Disease Models, Animal D005260:Female D015870:Gene Expression D017930:Genes, Reporter D016762:Genes, fos D005822:Genetic Vectors D009043:Motor Activity D009416:Nerve Regeneration D009474:Neurons D000076205:Ras Homolog Enriched in Brain Protein D051381:Rats D013119:Spinal Cord Injuries D014161:Transduction, Genetic
Rheb chondroitinase axon regeneration spinal cord injury peripheral nerve graft mTOR