Human ApoE and its Impact on Plasticity and Recovery After SCI

According to the National Spinal Cord Injury (SCI) Statistical Center there are an estimated 260,000 people in the United States with a spinal cord injury alongside 12,000 new cases each year. Associated costs to care for this debilitated population can exceed millions of dollars in addition to the emotional costs for those injured and their loved ones. There have been promising therapeutic approaches developed in pre-clinical animal models which promote central axon regeneration or plasticity leading to functional recovery. However, some of these interventions have failed to achieve complete translational success in the human population. What is not known is the reason for this failure. One potential factor is the varied genetic background of the human population which is not completely considered in these pre-clinical studies. Indeed, there might be a genetic predisposition or aversion towards rehabilitation and recovery after spinal cord injury that needs to be studied in order to fully realize the therapeutic application of these promising interventions. In this grant application, we propose to fill this gap in knowledge and examine genetic factors which can contribute to the success or failure of therapies targeting central nervous system plasticity and ultimately, functional restoration after SCI. One promising gene to investigate and which might impact these important processes used for recovery is the ApoE gene. Identified as a key genetic marker in predicting the development of Alzheimer’s Disease, its role in influencing the outcomes following neurotrauma and treatment has been severely understudied. In the lone human study investigating the importance of ApoE after SCI, it was determined that carrying the ApoE4 variant allele led to longer time in rehabilitation compared to those who carried the ApoE2 or 3 alleles. Moreover, the patients with ApoE4 had limited functional recovery compared to the other groups. Taken together, it is our central hypotheses that there are varying genetic dispositions towards sprouting and plasticity and that having the ApoE4 gene is a key limiting genetic determinant of these processes, as well as neurorestoration and recovery after SCI. As ApoE4 is prevalent in 20-24% of the human population, this is an important consideration. Having expertise in experimental spinal cord injury, plasticity, and regeneration, our research group is well positioned to build upon these initial findings, test our central hypotheses and elucidate the mechanisms behind the failure of regeneration, sprouting, and plasticity in human ApoE4+ animals. Ultimately, by recognizing that there may be genetic barriers to recovery, we can develop personalized therapies to target these populations and couple them with emerging therapeutic approaches aimed at treating SCI.