Lentiviral Gene Therapy for Artemis-Deficient SCID.

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Publication Year:
2022
Authors:
Morton J Cowan, Jason Yu, Janelle Facchino, Carol Fraser-Browne, Ukina Sanford, Misako Kawahara, Jasmeen Dara, Janel Long-Boyle, Jess Oh, Wendy Chan, Shivali Chag, Lori Broderick, Deepak Chellapandian, Helene Decaluwe, Catherine Golski, Diana Hu, Caroline Y Kuo, Holly K Miller, Aleksandra Petrovic, Robert Currier, Joan F Hilton, Divya Punwani, Christopher C Dvorak, Harry L Malech, R Scott McIvor, Jennifer M Puck
PubMed ID:
36546626
Public Summary:
Severe Combined Immunodeficiency (SCID) is a rare primary immunodeficiency in which patients lack T and B cells, the white blood cells needed to fight infections. Without a bone marrow stem cell transplant (HCT) from a donor to provide a healthy source of cells for the immune system, SCID patients typically die from infections in the 1st year of life. Artemis SCID (ART-SCID) is a rare form of SCID caused by defects in a gene called DCLRE1C that is essential for T and B cell development and repairing DNA damage. It is the most difficult type of SCID to treat with HCT, with best results using a tissue matched sibling donor, available for fewer than 20% of patients. Without a matched sibling donor, the risk of complications is higher than in other types of SCID. Even with a matched sibling donor, the immune system is often not fully restored, and many patients fail to develop B cells, requiring life-long antibody injections to stay healthy. In this study, babies with ART-SCID received treatment with “lentiviral gene transfer,” also called “gene therapy.” Stem cells are taken from a patient’s own bone marrow a normal copy of the DCLRE1C gene is inserted to provide correct instructions to the defective stem cells for developing working T and B cells. To make space in the bone marrow for the transplanted cells to grow, patients receive a chemotherapy drug called busulfan at 25% of the standard pre-HCT dose. This research aims to discover if gene therapy can successfully treat ART-SCID through investigating whether the procedure is safe, if it can be done using the gene transfer method, and if it will give children with ART-SCID a normal immune system. The first analysis was done after 10 babies were followed for an average of 2.6 years after gene therapy. No patients had unexpected side effects associated with busulfan or HCT. The corrected gene was present in all patients’ T cells at 6 to 16 weeks after transplant. Five of 6 patients followed for at least 24 months had T-cell immunity at around 12 months. Four of these patients developed enough B-cells or other indicators of immune recovery to stop antibody injections, with 3 then having normal responses to vaccines with vaccination underway for the 4th patient. One patient developed a severe infection before gene therapy and received a repeat gene therapy HCT to build enough T-cells to fight the infection. Four to 11 months after transplant 4 patients developed a potentially serious blood disorder called autoimmune hemolytic anemia, occurring when red blood cells are destroyed by antibodies the patient has inappropriately made, which resolved after sufficient T-cell immunity developed. All 10 patients were healthy at the time of the analysis. These promising early results demonstrate that infants with newly diagnosed ART-SCID who receive a transplant of their own gene-corrected cells after low dose busulfan can develop genetically corrected and functional T and B cells.
Scientific Abstract:
BACKGROUND: The DNA-repair enzyme Artemis is essential for rearrangement of T- and B-cell receptors. Mutations in DCLRE1C, which encodes Artemis, cause Artemis-deficient severe combined immunodeficiency (ART-SCID), which is poorly responsive to allogeneic hematopoietic-cell transplantation. METHODS: We carried out a phase 1-2 clinical study of the transfusion of autologous CD34+ cells, transfected with a lentiviral vector containing DCLRE1C, in 10 infants with newly diagnosed ART-SCID. We followed them for a median of 31.2 months. RESULTS: Marrow harvest, busulfan conditioning, and lentiviral-transduced CD34+ cell infusion produced the expected grade 3 or 4 adverse events. All the procedures met prespecified criteria for feasibility at 42 days after infusion. Gene-marked T cells were detected at 6 to 16 weeks after infusion in all the patients. Five of 6 patients who were followed for at least 24 months had T-cell immune reconstitution at a median of 12 months. The diversity of T-cell receptor beta chains normalized by 6 to 12 months. Four patients who were followed for at least 24 months had sufficient B-cell numbers, IgM concentration, or IgM isohemagglutinin titers to permit discontinuation of IgG infusions. Three of these 4 patients had normal immunization responses, and the fourth has started immunizations. Vector insertion sites showed no evidence of clonal expansion. One patient who presented with cytomegalovirus infection received a second infusion of gene-corrected cells to achieve T-cell immunity sufficient for viral clearance. Autoimmune hemolytic anemia developed in 4 patients 4 to 11 months after infusion; this condition resolved after reconstitution of T-cell immunity. All 10 patients were healthy at the time of this report. CONCLUSIONS: Infusion of lentiviral gene-corrected autologous CD34+ cells, preceded by pharmacologically targeted low-exposure busulfan, in infants with newly diagnosed ART-SCID resulted in genetically corrected and functional T and B cells. (Funded by the California Institute for Regenerative Medicine and the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT03538899.).