Overcoming Graft Rejection in Induced Pluripotent Stem Cell-Derived Inhibitory Interneurons for Drug-Resistant Epilepsy

Background: Cell-based therapies for drug-resistant epilepsy using induced pluripotent stem cell-derived inhibitory interneurons are now in early-phase clinical trials, building on findings from trials in Parkinson’s disease (PD) and Huntington’s disease (HD). Graft rejection and the need for immunosuppressive therapy post-transplantation pose potential barriers to more epilepsy patients becoming potential candidates for inhibitory interneurons transplantation surgery. Objectives: The present literature review weighs the evidence for and against human leukocyte antigen (HLA)-mediated graft rejection in PD and HD and examines the potential advantages and drawbacks to five broad approaches to cell-based therapies, including autologous cell culture and transplantation, in vivo reprogramming of glial cells using viral vectors, allogeneic transplantation using off-the-shelf cell lines, transplantation using inhibitory interneurons cultured from HLA-matched cell lines, and the use of hypoimmunogenic-induced pluripotent stem cell-derived inhibitory interneurons. The impact of surgical technique and associated needle trauma on graft rejection is also discussed. Methods: Non-systematic literature review. Results: While cell-based therapies have enjoyed early successes in treating a host of central nervous system disorders, the immunologic reaction against surgical procedures and implanted materials has remained a major obstacle. Conclusions: Adapting cell-based therapies using iPSC-derived inhibitory interneurons for epilepsy surgery will similarly require surmounting the challenge of immunogenicity.