Restoration of T and B Cell Differentiation after RAG1 Gene Transfer in Human RAG1 Defective Hematopoietic Stem Cells.
Nataël SorelFrancisco Díaz-PascualBoris BessotHanem SadekChloé MolletMyriam ChouteauMarco ZahnIrene Gil-FarinaParisa TajerMarja van EggermondDagmar BerghuisArjan C LankesterIsabelle AndréRichard GabrielMarina CavazzanaKasrin Pike-OverzetFrank J T StaalChantal Lagresle-PeyrouPublished in: Biomedicines (2024)
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 RAG 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 RAG1 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.
Keyphrases
- genome wide
- bone marrow
- stem cells
- genome wide identification
- gene therapy
- clinical trial
- end stage renal disease
- copy number
- endothelial cells
- newly diagnosed
- ejection fraction
- randomized controlled trial
- gene expression
- dna damage
- metabolic syndrome
- signaling pathway
- mesenchymal stem cells
- machine learning
- study protocol
- adipose tissue
- cell proliferation
- transcription factor
- skeletal muscle
- patient reported outcomes
- insulin resistance
- dna repair
- big data
- smoking cessation
- combination therapy
- electron transfer