Severe combined immunodeficiency (SCID) is an inherited immune disorder characterized by T-cell lymphopenia and profound lack of cellular and humoral immunity.The treatment for SCID is immune reconstitution, which includes hematopoietic stem cell (HSCT) transplantation or gene therapy. The disadvantage of HSCT is the need of an HLA matched donor. Utilization of T-cell depleted haploidentical bone marrow, unrelated bone marrow, or unrelated umbilical cord blood may cause morbidity and mortality due to graft vs. host disease and post transplantation immunosuppressive therapy. Gene therapy with genetically modified autologous cells offers a cure for X-SCID with significant immune reconstitution. The disadvantage is the possibility of leukemogenesis. Of ten infants with X-linked SCID treated with gene therapy in Paris, France, two developed T-cell leukemia.
Case Report A 3-year-old Caucasian male was diagnosed with X-SCID at birth by lymphopenia and an absent thymus. A missense mutation of IL-2R gamma C gene was identified at NIH. He received gene therapy at 3 months of age. Within 3 months, the lymphocyte count increased with normal number of T and B cells. Thirty-four months after treatment, the patient showed hyperleukocytosis, anemia, thrombocytopenia, and lymphoblasts on peripheral smear. Bone marrow biopsy confirmed T-cell leukemia with trisomy 10. He is currently on chemotherapy and in complete remission. The subsequent development of leukemia in the two children has raised concerns regarding the safety of gene therapy utilizing integrating vectors. Studies have been conducted using non-human primates and dogs. None developed abnormal hematopoiesis or leukemia. This may suggest that retroviral integrations using replication-incompetent vectors are unlikely to result in leukemogenesis and that patient or transgene specific factors most likely contributed to the occurrence of leukemia. Gene therapy is clearly a feasible therapeutic option for SCID, though it has also raised important questions regarding the long-term outcome.
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