While allogeneic HSCT is a mainstay of treatment and has had progressively improved outcomes, the immunological complications remain a major source of morbidity and potential mortality. Post-transplant, immune suppression is often given to prevent development of GVHD. In addition to pre-transplant myelosuppressive agents that open up space in the HSC niche, potent immune suppressive agents are often administered to minimize risks of donor cell rejection. However, immunological differences between the patient and the HSC donor may lead to significant complications, including rejection of the donor HSC graft or attack by the transferred donor's immune cells against the recipient – graft vs. Replacement of the patient's hematopoietic stem cells (HSC) that carry the defective PID-causing gene with allogeneic HSC from a healthy donor can lead to production of genetically normal blood cells and restore immunity. Further improvements in methods should lead to more consistent and reliable efficacy from gene therapy for a growing list of PIDs.Īllogeneic hematopoietic stem cell transplantation (HSCT) has been a definitive therapy for the most severe PIDs over the past 4–5 decades. In all, gene therapy for PIDs has progressed over the recent decades to be equal or better than allogeneic HSCT in terms of efficacy and safety. Gene therapy has successfully treated several PIDs including Adenosine Deaminase Severe Combined Immunodeficiency (SCID), X-linked SCID, Artemis SCID, Wiskott-Aldrich Syndrome, X-linked Chronic Granulomatous Disease and Leukocyte Adhesion Deficiency-I. These SIN vectors have excellent safety profiles and have not been reported to cause any clinically significant genotoxicity. More recent studies used lentiviral vectors in which the enhancer elements of the long terminal repeats self-inactivate during reverse transcription (“SIN” vectors). While these studies showed clinical efficacy in many cases, especially with the administration of marrow cytoreductive conditioning before cell re-infusion, these vectors caused genotoxicity and development of leukoproliferative disorders in several patients. Initial studies of gene therapy for PIDs in the 1990–2000's used integrating murine gamma-retroviral vectors. Gene therapy is an innovative treatment for Primary Immune Deficiencies (PIDs) that uses autologous hematopoietic stem cell transplantation to deliver stem cells with added or edited versions of the missing or malfunctioning gene that causes the PID. 2Division of Pediatric Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.1Division of Pediatric Allergy and Immunology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.
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