Co-Delivery of Sustained Release Chondroitinase ABC-37 With Human iPSC-Derived Neural Progenitors Promotes Transplant...

Stroke is a leading cause of disability worldwide, yet effective treatments to regenerate damaged tissue remain elusive. We investigated tissue regeneration and functional recovery post-stroke in an animal model with a combinatorial approach leveraging human induced pluripotent stem cell-derived neural progenitor cells (NPCs) and a sustained-release formulation of a re-designed, thermostable chondroitinase ABC (ChASE37). We optimized an in situ gelling, injectable hyaluronic acid (HA)-based hydrogel with the incorporation of laminin to deliver NPCs to the cavity in a rat model of sub-acute ischemic stroke. We delivered ChASE37 by affinity release from a methylcellulose hydrogel (ChASE37-AR) to the stroke-injured brain by epicortical injection. ChASE37-AR retained long-term enzymatic activity, as demonstrated by degradation of inhibitory chondroitin sulfate proteoglycans (CSPGs) in the injured tissue, with no evidence of immunogenicity. Each treatment - ChASE37-AR, NPCs, and their co-delivery - significantly improved motor function as early as 3 weeks after a single administration. Critically, only the combined therapy supported long-term survival and neuronal differentiation of transplanted cells, suggesting that ChASE37-AR has a role beyond CSPG degradation. This strategy presents a modular, clinically relevant platform for tissue regeneration post-stroke. Together, these findings suggest that the co-delivery of NPCs and sustained-release ChASE37 may be promising for stroke treatment.