Immune Reconstitution After Gene Therapy Approaches in Patients With X-Linked Severe Combined Immunodeficiency Disease

Abstract

X-linked severe immunodeficiency disease (SCID-X1) is an inherited, rare, and life-threating disease. The genetic origin is a defect in the interleukin 2 receptor γ chain (IL2RG) gene and patients are classically characterized by absence of T and NK cells, as well as presence of partially-functional B cells. Without any treatment the disease is usually lethal during the first year of life. The treatment of choice for these patients is hematopoietic stem cell transplantation, with an excellent survival rate (>90%) if an HLA-matched sibling donor is available. However, when alternative donors are used, the success and survival rates are often lower. Gene therapy has been developed as an alternative treatment initially using γ-retroviral vectors to correct the defective γ chain in the absence of pre-conditioning treatment. The results were highly promising in SCID-X1 infants, showing long-term T-cell recovery and clinical benefit, although NK and B cell recovery was less robust. However, some infants developed T-cell acute lymphoblastic leukemia after the gene therapy, due to vector-mediated insertional mutagenesis. Consequently, considerable efforts have been made to develop safer vectors. The most recent clinical trials using lentiviral vectors together with a low-dose pre-conditioning regimen have demonstrated excellent sustained T cell recovery, but also B and NK cells, in both children and adults. This review provides an overview about the different gene therapy approaches used over the last 20 years to treat SCID-X1 patients, particularly focusing on lymphoid immune reconstitution, as well as the developments that have improved the process and outcomes.

DAP10 Predicted the Outcome of Pediatric B-Cell Acute Lymphoblastic Leukemia and Was Associated with the T-Cell Exhaustion

“…Moreover, we found that IL2RG and IL2RB significantly decreased after DAP10 downregulation. Since these two proteins were crucial in the intracellular signaling during the activation process of CD8+ T cells [ 28 , 29 ], we supposed that CD8+ T cells in DAP10 low expression patients could not transmit downstream signals to the nucleus when exposed to the antigen, which led to the blockade of activation of CD8+ T cells.…”

Case Report: Interleukin-2 Receptor Common Gamma Chain Defect Presented as a Hyper-IgE Syndrome

“…Typically, patients with genetic mutations of the IL2RG gene are classically characterized by the absence or severe reduction of T and NK cell numbers, as well as the presence of non-functional B cells ( 33 ), these mutations are mainly localized within the exons 3-5 ( 34 , 35 ). Missense mutations are the most common pathogenic changes observed, followed by nonsense variants and insertions/deletions ( 35 ).…”

Advanced Therapy Medicinal Products' Translation in Europe: A Developers' Perspective

“…These concerns were highlighted by a gene therapy trial to treat children with X-linked severe combined immunodeficiency. Some of the patients developed acute lymphoblastic T-cell leukemia following gene therapy, due to vector-mediated insertional mutagenesis ( 27 , 28 ). The governance of novel technologies such as designer nucleases, e.g., CRISPR/Cas9 technology, require the development of advanced strategies to identify potential complications such as off-target editing or immunogenicity.…”