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 sibling donor whose stem cells closely match those of the patient. This type of donor is generally available for less than 20% of patients. Without a matched sibling donor, the risk of complications is higher than in other types of SCID. Even with such a 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. 

We are studying a new type of HCT to treat ART-SCID. Participants consisted of two separate groups of patients, babies who were newly diagnosed with ART-SCID and older patients who had already received a transplant from a donor, but had not subsequently developed a healthy immune system. Both groups received treatment with “lentiviral gene transfer,” also called “gene therapy.” For this treatment, stem cells are taken from a patient’s own bone marrow, and a normal copy of the DCLRE1C gene is inserted in the cells. The DCLRE1C gene then provides correct instructions for developing working T and B cells to the defective stem cells. To make space in the bone marrow for the transplanted cells to grow, patients receive a chemotherapy drug called busulfan at 20-25% of the standard dose for HCT from donors. Our aim is to discover if gene therapy can successfully treat ART-SCID through looking at whether the procedure is safe, if it can be done using the gene transfer method, and if it will give normal immune systems to children with ART-SCID. As of November 2024, 17 newly diagnosed babies and 3 older patients have participated in the study.

We looked at results in newly diagnosed babies after the first 10 patients in this group had been followed after gene therapy for an average of 2.6 years. No patients had unexpected side effects associated with busulfan or stem cell transplant. The corrected gene was present in all 10 patients’ T and B cells at 6 to 16 weeks after transplant. Five of 6 patients followed for at least 24 months had normal 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, and vaccination still underway for the 4^th patient at the time of this analysis. One patient developed a severe infection before gene therapy and received a repeat gene therapy transplant to build enough T-cells to fight the infection. Four to 11 months after transplant, 4 patients developed a potentially serious blood disorder (also a complication of bone marrow transplants from healthy donors), 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 results were published in the New England Journal of Medicine in 2022 (PMID: 36546626).

Gene therapy has been less successful for treating the older patients who had already had a standard donor transplant. These 3 patients had mixed results, with only one patient developing lasting B cells and one patient dying from complications related to her underlying ART-SCID. Both remaining previously treated patients continue to need regular antibody injections more than 5 years after gene therapy. The reasons why their outcomes were different from the babies is still unknown, but one factor could be that all the previously treated patients had health problems related to ART-SCID before having gene therapy. 

In September 2024 we revised the study to include only newly diagnosed babies, and plan to investigate gene therapy for previously treated patients in a future, separate study. Once enough newly diagnosed patients have been treated and followed, we will apply for FDA approval for this type of gene therapy. Our aim is to make this promising treatment widely available to newly diagnosed ART-SCID patients.