Enhancing the Reparative Efficacy of Schwann Cells following Chronic SCI

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DESCRIPTION Chronic spinal cord injury (SCI) affects more than 1.25 million people in the United States, with more than 11,000 new injuries sustained annually. Recovery is limited because severed axons of the adult mammalian central nervous system (CNS) are unable to regenerate. Of the multiple treatment strategies employed in experimental models for SCI repair, cellular grafting to bridge the injury site and provide a substrate for axonal re-growth has been a foundation for many of the promising acute, sub-acute and chronic therapies. Our work to date has focused on the utility of the Schwann cell (SC), a peripheral glial cell critical for peripheral nerve regeneratio and repair, to anatomically and functionally restore the injured spinal cord. SCs can facilitate anatomical repair and improvements in functional recovery in a number of experimental SCI models (complete and incomplete; cervical and thoracic; acute and chronic). Importantly, SCs could be obtained from a peripheral nerve biopsy from a SCI individual, purified and expanded to large numbers in culture for ensuing autologous implantation. It is because of these beneficial effects that The Miami Project recently submitted to The Food and Drug Administration an Investigational New Drug Application to request permission to undertake a Phase 1 clinical trial with autologous SCs for sub-acute human SCI repair. Despite this success, the fact remains that SC migration is very limited within the injured spinal cord, which is likely to significantly lessen their therapeutic efficacy. A lack of migration limits the ability of SCs to guide axons bot into and from the lesion as well as prevents SCs from reaching regions of distal demyelination so as to facilitate re-myelination repair. It therefore occurred to us that the ability of cell surace polysialylic acid (PSA) to facilitate cell migration during normal development might be exploited in the SC translational approach. We have recently shown in sub-acute SCI that SCs can readily migrate within the injured spinal cord when they have been genetically modified to express high levels of PSA, and that this SC modification leads to significantly greater axon regeneration and functional restitution following SCI. The next step in our work, as represented in this proposal, is to move closer to therapeutic relevance through the optimization and extension of the use of PSA in SCI, particularly to the treatment of chronic SCI. The research plan seeks to achieve that goal first by improvement in the practicality of the PSA-SC approach through the use of the purified polysialyltransferase (obtained from bacteria) to synthesize PSA directly on SCs and/or axons, thus avoiding the use of gene therapy in experimental paradigms of sub-acute and chronic SCI (Specific Aim 1). The proposal then seeks to understand the mechanism(s) by which PSA alters the migratory capacity of Schwann cells and improves the axon growth promoting ability of Schwann cells. (Specific Aim 2). As the ultimate goal of this work is to improve SCI repair in vivo, these studies will be evaluated not only in terms of the cel and tissue biology of our manipulations, but also the effect of those procedures on functional outcomes as measured in extensive behavioral testing. The proposed work will provide important data to allow us to expand the scope of our initial clinical trial with SCs from sub-acut to chronic SCI as well as provide readily translatable combinatory approaches that can putatively enhance the effectiveness of SCs clinically in both sub-acute and chronic SCI.