CHONDROITINASE ABC MUTANTS AND METHODS OF MANUFACTURE AND USE THEREOF

摘要

The present application provides a Chondroitinase ABC (ChABC) mutants. ChABC stimulates axonal regeneration by degrading the inhibitory chondroitin sulfate (CS) and dermatan sulfate (DS) proteoglycans in the glial scar that forms after traumatic injuries to the central nervous system (CNS). However, the therapeutic utility of this potent, fragile protein is severely limited by rapid aggregation at physiological temperature. To overcome this limitation, the ChABC mutants were engineered to at least 15 point mutations in domain 2 of the wild-type ChABC and/or at least 5 point mutations in domain 3 of the wild-type enzyme. These mutants exhibit improved stability over wild-type ChABC. The present application further provides method and compositions comprising the mutant ChABC for treating conditions associated with excess proteoglycan formation or conditions for which treatment is benefitted by degradation of proteoglycans, including CNS injuries, scarring and cancer.