Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID

Overview

Journal Mol Ther Methods Clin Dev

Publisher Cell Press

Date 2020 Apr 24

PMID 32322605

Citations 34

Authors

Laura Garcia-Perez

Marja van Eggermond

Lieke van Roon

Sandra A Vloemans

Martijn Cordes

Axel Schambach

Michael Rothe

Dagmar Berghuis

Chantal Lagresle-Peyrou

Marina Cavazzana

Fang Zhang

Adrian J Thrasher

Daniela Salvatori

Pauline Meij

Anna Villa

Jacques J M van Dongen

Jaap-Jan Zwaginga

Mirjam van der Burg

H Bobby Gaspar

Arjan Lankester

Frank J T Staal

Karin Pike-Overzet

Affiliations

Soon will be listed here.

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 to ensure optimal expression. We used 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 expression. Mice with low 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.

Citing Articles

Synthetic Promoters in Gene Therapy: Design Approaches, Features and Applications.

Artemyev V, Gubaeva A, Paremskaia A, Dzhioeva A, Deviatkin A, Feoktistova S Cells. 2024; 13(23).

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[Advances in gene therapy for inborn errors of immunity].

Li T, Song H Zhongguo Dang Dai Er Ke Za Zhi. 2024; 26(8):865-870.

PMID: 39148393 PMC: 11334546. DOI: 10.7499/j.issn.1008-8830.2404027.

Restoration of T and B Cell Differentiation after RAG1 Gene Transfer in Human RAG1 Defective Hematopoietic Stem Cells.

Sorel N, Diaz-Pascual F, Bessot B, Sadek H, Mollet C, Chouteau M Biomedicines. 2024; 12(7).

PMID: 39062069 PMC: 11275127. DOI: 10.3390/biomedicines12071495.

Utilizing epigenetic regulators to improve HSC-based lentiviral gene therapy.

Tajer P, Karakaslar E, Cante-Barrett K, Naber B, Vloemans S, van Eggermond M Blood Adv. 2024; 8(18):4936-4947.

PMID: 38916861 PMC: 11421325. DOI: 10.1182/bloodadvances.2024013047.

Mending RAG2: gene editing for treatment of RAG2 deficiency.

Hicks E, Keller M Blood Adv. 2024; 8(7):1817-1819.

PMID: 38592712 PMC: 11006806. DOI: 10.1182/bloodadvances.2023012079.

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