Combination treatment with chondroitinase ABC in spinal cord injury—breaking the barrier

Abstract

After spinal cord injury (SCi), re-establishing functional circuitry in the damaged central nervous system (CNS) faces multiple challenges including lost tissue volume, insufficient intrinsic growth capacity of adult neurons, and the inhibitory environment in the damaged CNS. Several treatment strategies have been developed over the past three decades, but successful restoration of sensory and motor functions will probably require a combination of approaches to address different aspects of the problem. Degradation of the chondroitin sulfate proteoglycans with the chondroitinase ABC (ChABC) enzyme removes a regeneration barrier from the glial scar and increases plasticity in the CNS by removing perineuronal nets. its mechanism of action does not clash or overlap with most of the other treatment strategies, making ChABC an attractive candidate as a combinational partner with other methods. in this article, we review studies in rat SCi models using ChABC combined with other treatments including cell implantation, growth factors, myelin-inhibitory molecule blockers, and ion channel expression. We discuss possible ways to optimize treatment protocols for future combinational studies. To date, combinational therapies with ChABC have shown synergistic effects with several other strategies in enhancing functional recovery after SCi. These combinatorial approaches can now be developed for clinical application.

One-year clinical study of NeuroRegen scaffold implantation following scar resection in complete chronic spinal cord injury patients

“…This leads to con- (Cregg et al, 2014;Lukovic et al, 2015;Silver and Miller, 2004). Chondroitinase ABC (ChABC) can enzymatically digest the glycosaminoglycan side-chains of CSPGs, and ChABC treatment could improve glial scar digestion to reduce the lesion size and increase neural regeneration, which might further promote functional recovery in rat SCI (Barritt et al, 2006;Bradbury and Carter, 2011;Zhao and Fawcett, 2013). However, studies assessing the efficacy of ChABC treatment have only been performed in small animal models.…”

Electrical Stimulation to Enhance Axon Regeneration After Peripheral Nerve Injuries in Animal Models and Humans

“…The discrepancy between the elevated cAMP and the efficacy of the electrical stimulation in promoting axon outgrowth suggested additional mechanisms to account for the greater effect of the conditioning lesion than the electrical stimulation [86]. The suppressed ability of axotomized sensory neurons to upregulate growth-associated proteins (GAPs) when their central axons are injured is 1 of the 2 reasons why the axons do not normally regrow their lost axons, the other being the presence of the oligodendrocytes rather than Schwann cells in the CNS and the proteoglycans that directly inhibit axon extension [105][106][107][108]. Only when GAPs are expressed as they are after proximal CNS nerve lesions for example, do the CNS axons regrow [109,110].…”

Canine olfactory ensheathing cells from the olfactory mucosa can be engineered to produce active chondroitinase ABC

“…Our aim is to develop a new therapy that combines the beneficial effects of a cell transplant while allowing sustained delivery of ChABC into the site of SCI. It is generally agreed that combining therapies for SCI is likely to be more efficient than a single therapy to repair complex lesions affecting patients (32)(33)(34). ChABC is likely to form an essential component of any combination therapy because of its pleotrophic actions that compliment most other SCI therapies.…”