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Lentiviral Gene Therapy for Artemis-Deficient SCID
Morton J Cowan1, Jason Yu1, Janelle Facchino1
1From the Departments of Pediatrics (M.J.C., J.Y., J.F., C.F.-B., U.S., M.K., J.D., J.L.-B., W.C., S.C., R.C., C.C.D., J.M.P.) and Epidemiology and Biostatistics (J.F.H.), the Smith Cardiovascular Research Institute (M.J.C., J.M.P.), and the School of Pharmacy (J.L.-B.), University of California, San Francisco (UCSF), and UCSF Benioff Children's Hospital (M.J.C., J.F., J.D., J.L.-B., J.O., C.C.D., J.M.P.), San Francisco, the Department of Pediatrics, University of California, San Diego, and Rady Children's Hospital, San Diego (L.B.), and the Department of Pediatrics, UCLA Mattel Children's Hospital, Los Angeles (C.Y.K.) - all in California; the Department of Pediatrics, Johns Hopkins All Children's Hospital, St. Petersburg, FL (D.C.); the Department of Pediatrics, Sainte-Justine University Hospital Center, University of Montreal, Montreal (H.D.); Tuba City Regional Health Care, Tuba City (C.G., D.H.), and Phoenix Children's Hospital, Phoenix (H.K.M.) - both in Arizona; the Department of Pediatrics, University of Washington Seattle Children's Hospital, Seattle (A.P.); Clinical Development, Roche Diagnostics Solutions, Singapore (D.P.); the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (H.L.M.); and the Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis (R.S.M.).
Gene therapy successfully restored T and B cells in infants with Artemis-deficient severe combined immunodeficiency (ART-SCID). This treatment offers a promising new approach for ART-SCID, improving immune function and patient health.
Area of Science:
- Immunology
- Gene Therapy
- Hematology
Background:
- Artemis (DNA-repair enzyme) is crucial for T- and B-cell receptor rearrangement.
- Mutations in DCLRE1C gene cause Artemis-deficient severe combined immunodeficiency (ART-SCID).
- ART-SCID is poorly responsive to traditional hematopoietic-cell transplantation.
Purpose of the Study:
- To evaluate the safety and efficacy of lentiviral gene therapy for ART-SCID.
- To assess immune reconstitution in infants with ART-SCID following gene-corrected CD34+ cell transfusion.
Main Methods:
- Phase 1-2 clinical study involving 10 infants with newly diagnosed ART-SCID.
- Autologous CD34+ cells were transfected with a lentiviral vector containing DCLRE1C.
- Patients underwent marrow harvest, busulfan conditioning, and gene-corrected cell infusion.
Main Results:
- Feasibility criteria met; Grade 3/4 adverse events as expected.
- Gene-marked T cells detected in all patients; immune reconstitution observed in most.
- Normalized T-cell receptor diversity and improved B-cell function achieved.
- No evidence of clonal expansion from vector insertion sites; manageable autoimmune complications.
Conclusions:
- Lentiviral gene therapy effectively produces genetically corrected and functional T and B cells in ART-SCID infants.
- This approach, with targeted busulfan conditioning, shows promise for treating ART-SCID.
- All 10 patients were healthy at the report's conclusion, indicating treatment success.
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