Garcia-Perez, L;
Van Eggermond, M;
Van Roon, L;
Vloemans, SA;
Cordes, M;
Schambach, A;
Rothe, M;
... Pike-Overzet, K; + view all
(2020)
Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID.
Molecular Therapy: Methods & Clinical Development
, 17
pp. 666-682.
10.1016/j.omtm.2020.03.016.
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Abstract
Recombinase-activating gene-1 (RAG1)-deficient severe combined immunodeficiency (SCID) patients lack B and T lymphocytes due to the inability to rearrange immunoglobulin and T cell receptor genes. Gene therapy is an alternative for those RAG1-SCID patients who lack a suitable bone marrow donor. We designed lentiviral vectors with different internal promoters driving codon-optimized RAG1 to ensure optimal expression. We used Rag1−/− mice as a preclinical model for RAG1-SCID to assess the efficacy of the various vectors. We observed that B and T cell reconstitution directly correlated with RAG1 expression. Mice with low RAG1 expression showed poor immune reconstitution; however, higher expression resulted in phenotypic and functional lymphocyte reconstitution comparable to mice receiving wild-type stem cells. No signs of genotoxicity were found. Additionally, RAG1-SCID patient CD34+ cells transduced with our clinical RAG1 vector and transplanted into NSG mice led to improved human B and T cell development. Considering this efficacy outcome, together with favorable safety data, these results substantiate the need for a clinical trial for RAG1-SCID.
| Type: | Article |
|---|---|
| Title: | Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.omtm.2020.03.016 |
| Publisher version: | https://doi.org/10.1016/j.omtm.2020.03.016 |
| Language: | English |
| Additional information: | Copyright © 2020 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | gene therapy, SCIDB lymphocytes, T lymphocytes, CD34+ cells, gene rearrangement, RAG1, lentiviral vector |
| 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/10095771 |
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