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

Blanco, E; Izotova, N; Booth, C; Thrasher, AJ; (2020) Immune Reconstitution After Gene Therapy Approaches in Patients With X-Linked Severe Combined Immunodeficiency Disease. Frontiers in Immunology , 11 , Article 608653. 10.3389/fimmu.2020.608653. Green open access

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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.

Type: Article
Title: Immune Reconstitution After Gene Therapy Approaches in Patients With X-Linked Severe Combined Immunodeficiency Disease
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fimmu.2020.608653
Publisher version: http://dx.doi.org/10.3389/fimmu.2020.608653
Language: English
Additional information: Copyright © 2020 Blanco, Izotova, Booth and Thrasher. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Keywords: X-linked severe immunodeficiency disease, gene therapy, immune reconstitution, clinical trial, T cells, B&#160, cells, NK cells, conditioning, STEM-CELL TRANSPLANTATION, CONSORTIUM INTERNATIONAL-CONFERENCE, HEMATOPOIETIC PROGENITOR CELLS, INACTIVATING LENTIVIRAL VECTOR, LEUKEMIA-VIRUS INTEGRATION, 2ND PEDIATRIC BLOOD, COMMON GAMMA-CHAIN, LONG-TERM, INSERTIONAL MUTAGENESIS, BONE-MARROW
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10118463
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