Gene Therapies for Primary Immune Deficiencies

Abstract

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. Initial studies of gene therapy for PIDs in the 1990-2000's used integrating murine gamma-retroviral 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. More recent studies used lentiviral vectors in which the enhancer elements of the long terminal repeats self-inactivate during reverse transcription ("SIN" vectors). These SIN vectors have excellent safety profiles and have not been reported to cause any clinically significant genotoxicity. 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. 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. Further improvements in methods should lead to more consistent and reliable efficacy from gene therapy for a growing list of PIDs.

Keywords: gene therapy; hematopoietic stem cell; lentiviral vector; primary immune deficiency; retroviral vector.

Figure 1

Gene therapy corrects PIDs by restoring the affected blood cells. HSPC, hematopoietic progenitor and stem cells; BM, bone marrow; PBSC, peripheral blood stem cells; GMP, good manufacturing practice laboratory; HSC, hematopoietic stem cells; CGD, Chronic Granulomatous Disease; LAD-1, Leukocyte Adhesion Deficiency-I; X-ALD, X-linked Adrenoleukodystrophy; MLD, metachromatic Leukodystrophy; MPS, Mucopolysaccharidoses; Thal, α- or β-Thalassemia; WAS, Wiskott-Aldrich Syndrome; SCID, Severe Combined Immune Deficiency; HLH, Hemophagocytic Lymphohistiocytosis; IPEX, Immune Deficiency Polyendocrinopathy, X-Linked; XHIM, X-linked Hyper IgM; XLP, X linked Lymphoproliferative. Diseases in bold font are currently in clinical trials. Parenthesis () mark non-PIDs.