OPTIMIZATION OF INTRACELLULAR SIGMA PEPTIDE AS A TREATMENT FOR SPINAL CORD INJURY
Regeneration and sprouting following spinal cord injury is curtailed by several processes, with the inhibitory chondroitin-sulfate proteoglycan (CSPG)-rich glial scar and peri-neuronal net being major impediments. We designed a small membrane-permeable peptide modulator of the CSPG receptor PTPσ (Intracellular Sigma Peptide, ISP), which was capable of blocking CSPG mediated inhibition in vitro 1-3. Delivered systemically over several weeks, ISP treatment restored coordinated walking and urinary function following contusive SCI in a large percentage of animals. We sought to optimize ISP for translational development. Following a T8 contusion injury (Infinite Horizon Impactor, 250kDyne), we treated animals daily with increasing doses of ISP, from 3.3µg to 44µg, for 7 weeks (n=5/dose). Escalating ISP to 44µg/day (4x of previous dose) led to a dramatic improvement in urinary function, with all animals recovering function. This suggests that increasing ISP efficacy, either through increased concentration or direct delivery paradigms may further enhance urinary recovery. We hypothesize that combinatorial therapies in conjunction with ISP, including a variety of neuroprotective and rehabilitation strategies, will be necessary to promote maximal recovery. Our data provide strong verification of the role of CSPGs and PTPσ in regeneration/sprouting failure following neurological trauma.
BT Lang1,2, JM Cregg2, A Tran2, MA DePaul2, BP Brown2, SA Busch1, Y Shen3, RW Mays1, and J Silver2 1 Athersys, 3201 Carnegie Avenue, Cleveland, OH 44115 2 Case Western Reserve University, Department of Neurosciences, Cleveland, OH 44106 3 The Ohio State University, Center for Brain and Spinal Cord Repair, Department of Neuroscience, Columbus, OH 43210