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Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID
- Source :
- Molecular Therapy: Methods & Clinical Development, Vol 17, Iss, Pp 666-682 (2020), Molecular Therapy-Methods & Clinical Development, Molecular Therapy-Methods and Clinical Development, 17, 666-682. CELL PRESS, Molecular Therapy. Methods & Clinical Development
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
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.<br />Graphical Abstract<br />A self-inactivating lentiviral vector was developed that functionally corrected Rag1 deficiency in a murine disease model and in RAG1-SCID patient cells. After X-linked and ADA SCID, RAG1-SCID is the third most frequent form of SCID, for which gene therapy may now become available.
- Subjects :
- 0301 basic medicine
lcsh:QH426-470
Genetic enhancement
Lymphocyte
T lymphocytes
gene rearrangement
chemical and pharmacologic phenomena
SCID
Article
Recombination-activating gene
Viral vector
03 medical and health sciences
0302 clinical medicine
immune system diseases
hemic and lymphatic diseases
Genetics
medicine
lcsh:QH573-671
Molecular Biology
Severe combined immunodeficiency
lcsh:Cytology
business.industry
lentiviral vector
hemic and immune systems
Gene rearrangement
medicine.disease
gene therapy
CD34+ cells
3. Good health
lcsh:Genetics
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Cancer research
Molecular Medicine
RAG1
Bone marrow
Stem cell
business
tissues
B lymphocytes
Subjects
Details
- ISSN :
- 23290501
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- Molecular Therapy - Methods & Clinical Development
- Accession number :
- edsair.doi.dedup.....5122d1f6ddad3ab4c2eece5461f222f3