The 3 patients with the highest gene marking in granulocytes consistently had the best cellular and clinical correction, the highest number of unique vector insertions, and the most polyclonal repertoire (see figure).ĪDA SCID stands in stark contrast to other inherited immunodeficiencies where gammaretroviral gene therapy was used, in that insertional oncogenesis has been very rarely seen. These biochemical and immunological parameters were strongly correlated with vector copy number in granulocytes with the 10 patients falling into low, medium, and high gene-marking categories. All patients expressed the ADA enzyme, with improvement in metabolic profile, T, B, and natural killer cell counts, immunoglobulin production, and 9 of 10 remained off enzyme replacement therapy. 1 The group also demonstrates that lymphocytes carrying the gene exhibit a strong selective advantage (see figure), with higher and more even gene marking (10-fold difference between patients) compared with granulocytes, a surrogate for gene marking in long-term hematopoietic stem cells (∼100-fold difference between patients). All 10 patients show stable multilineage gene marking 8 to 11 years post-treatment. Patients in this trial reported by Reinhardt et al received transduced bone marrow cells that were infused fresh without cryopreservation, and transduction efficiency (measured as average vector copy number in bulk cultured CD34 + cells) was assessed in retrospect, with great variability from product to product. These trials all used gammaretroviral vectors in which the viral genes were replaced with a complementary DNA expressing the human ADA gene, leading to strong expression of the ADA enzyme controlled by the gammaretroviral regulatory elements. 2-4 Enzyme replacement therapy was paused before infusion and, importantly, patients received low-dose busulfan (or melphalan in London) to partially ablate recipient hematopoietic stem cells. After multiple attempts that failed because of poor efficiency of gene transfer and failure to sustain gene marking at a level with clinical benefit, groups in the United States, Italy, and London made 2 key changes in the protocol that made the difference between success and failure. Reinhardt et al show sustained efficacy from one of the first successful trials of gene therapy for inherited immune deficiency, and indeed for any disease.
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