A Narrative Review of Combination Therapies with Chondroitinase ABC in Preclinical Spinal Cord Injury Models

Abstract

Spinal cord injuries (SCI) initiate a secondary injury cascade that culminates in a chondroitin sulfate proteoglycan (CSPG)-rich glial scar, a major barrier to axon regeneration and circuit repair. Despite advances in rehabilitation strategies including electrotherapy and physical therapy, SCI continues to cause substantial and lasting motor impairment. Chondroitinase ABC (ChABC), a bacterial enzyme that cleaves the inhibitory glycosaminoglycan side chains of CSPGs, transiently converts this hostile matrix into a growth-permissive environment and reopens a window of neural plasticity. As a single agent, however, ChABC faces important limitations: the native enzyme is thermally unstable, its effects are transient, and anatomical sprouting does not reliably translate into durable functional recovery. This narrative review synthesizes 44 sources published between 2005 and 2025—preclinical SCI studies, supplemented by selected stroke-model, in vitro, and computational studies—to examine how pairing ChABC with a second modality may address these limitations. This review evaluates ChABC paired with rehabilitation, electrical stimulation, cell transplantation, growth factors, and antibody or molecular co-therapy in preclinical SCI models. Across these modalities, ChABC may act as an enabler that opens a permissive window for an activity- or growth-driven partner, or as a complementary agent that addresses additional inhibitory mechanisms. Novel delivery strategies may improve ChABC stability, localization, or therapeutic performance. Reported benefits of dual-modality approaches support investigating triple-modality regimens, although any additional benefit requires direct comparative evaluation. Overall, these findings support further preclinical investigation of appropriately designed and timed ChABC combinations, with optimization and standardization of delivery, dosing, and treatment timing representing key priorities for translational research. Clinical benefit in humans is not established by the reviewed evidence.