Efficacy of a biopolymer-based depot system of therapeutic protein in treatment of spinal cord injuries
Neurons in post-traumatized mammalian central nervous system show only limited degree of regeneration, which can be attributed to the presence of neurite outgrowth inhibitors in damaged myelin and glial scar, and to the apoptosis of severed central neurons and glial cells during secondary Wallerian degeneration. RhoA GTPase has been implicated as the common denominator in these counter-regeneration events, which shows significant and persistent up-regulation for weeks in injured spinal cord and cerebral infarct after stroke. While the exoenzyme C3 transferase is a potent RhoA inhibitor, its extremely low efficiency of cell entry and degradation in vivo has restricted the therapeutic value. To address these issues, a microsphere-based controlled release system of cell permeable C3 has previously been developed in our laboratory, which showed efficiently cell entry as early as 6 hours of incubation. Release profile of the encapsulated protein displayed a mild initial burst release of 25%, followed by a subsequent average daily release of 2.3% of encapsulated protein over one month, matching the change in RhoA level in severed brain and spinal cord. Importantly, TAT-C3 released from the microspheres remained active up to the first three weeks of incubation. The feasibility of this therapeutic agent in promoting axonal regeneration and functional recovery after spinal injury in rat will be assessed in this project.