Making space for cures: Conditioning for autologous hematopoietic stem cell gene therapies.

Abstract

Although allogeneic hematopoietic stem cell transplantation has long been the only curative therapy for nonmalignant blood diseases, recent clinical successes have demonstrated the transformative potential of autologous gene therapies as definitive treatments for these disorders. By providing durable life-changing clinical benefit while reducing the need for suitable allogeneic donors and avoiding immunologic complications like graft rejection and graft-versus-host disease, autologous transplantation with genetically modified hematopoietic stem cells provides a potentially safer and, in some respects, more accessible pathway to cure. However, several formidable barriers still prevent broader use of autologous gene therapy, including the risk of adverse acute and chronic effects from the busulfan-based conditioning regimens used to deplete host hematopoietic stem cells before transplant. In this article, we define the role transplant conditioning regimens play in autologous gene therapy, including contrasting the goals of care in this setting with those for stem cell transplantation for malignancies. We also discuss the conditioning strategies that are used by approved and select investigational autologous gene therapies to date, while highlighting exciting preclinical and clinical advances aimed at making transplant conditioning safer for myriad nonmalignant and malignant disease applications.