91 - Gene Therapy for Primary Immune Deficiency Diseases

Abstract

Many severe primary immune deficiencies (PIDs) are due to defects in lymphoid or hematopoietic cells that can be reconstituted by transplantation of normal hematopoietic stem cells (HSCs). Allogeneic hematopoietic stem cell transplantation (HSCT) has been successfully applied to more than a dozen human PIDs, limited by the need for a well-matched donor and the potential to develop graft-versus-host disease (GvHD). Gene therapy using autologous HSCs has been developed as a new treatment for these PIDs, with potential advantages from the absence of GvHD and the less intense conditioning and immune suppression needed. In the early years (c. 1990–1999), sufficient gene transfer to HSC was not achieved and no efficacy was seen. Subsequently (c. 2000–2010), several clinical trials of gene therapy for PIDs using γ-retroviral vectors showed effective immune reconstitution; however, some of these patients developed myelodysplasia or leukemia due to genotoxicity from the retroviral vectors. Currently, improved vectors modified to minimize risks of genotoxicity are being used safely and effectively in clinical trials for a growing list of PIDs. More recently, methods are being established for direct genome editing to correct the specific gene underlying a PID in the genome of autologous HSC. Gene editing may have broader applications to the PIDs where precise gene expression regulation is needed for safety and efficacy. The advances in gene therapy will be compared to those ongoing for allogeneic HSCT approaches to define optimal treatments for severe PID.