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

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2024 Jul 27

PMID 39062069

Authors

Natael Sorel

Francisco Diaz-Pascual

Boris Bessot

Hanem Sadek

Chloe Mollet

Myriam Chouteau

Marco Zahn

Irene Gil-Farina

Parisa Tajer

Marja van Eggermond

Dagmar Berghuis

Arjan C Lankester

Isabelle Andre

Richard Gabriel

Marina Cavazzana

Kasrin Pike-Overzet

Frank J T Staal

Chantal Lagresle-Peyrou

Affiliations

Soon will be listed here.

Abstract

Recombinase-activating gene (RAG)-deficient SCID patients lack B and T lymphocytes due to the inability to rearrange immunoglobulin and T cell receptor genes. The two genes act as a required dimer to initiate gene recombination. Gene therapy is a valid treatment alternative for RAG-SCID patients who lack a suitable bone marrow donor, but developing such therapy for RAG1/2 has proven challenging. Using a clinically approved lentiviral vector with a codon-optimized gene, we report here preclinical studies using CD34+ cells from four RAG1-SCID patients. We used in vitro T cell developmental assays and in vivo assays in xenografted NSG mice. The RAG1-SCID patient CD34 cells transduced with the RAG1 vector and transplanted into NSG mice led to restored human B and T cell development. Together with favorable safety data on integration sites, these results substantiate an ongoing phase I/II clinical trial for RAG1-SCID.

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