In all five reported cases ( n = 4 of 10 children in the Paris trial and n = 1 of 10 in the London trial), T-cell acute lymphoblastic leukemia occurred as a direct consequence of insertional mutagenesis by the retroviral vector used to deliver the therapeutic gene ( 20, 21, 22, 23, 24). However, the development of leukemia has appeared as a severe adverse effect in both trials ( 19). Immunodeficiency was restored and lymphocyte development was no longer blocked. Both X-linked SCID trials have been highly successful in many ways, showing long-lasting restoration of immunity. The two gene therapy trials for X-linked SCID have shown the clinical feasibility of introducing a therapeutic gene into hematopoietic stem cells (HSCs) ( 8, 9). This work is covered by a number of excellent reviews ( 13, 14, 15, 16, 17, 18), but will be briefly discussed here because of its relevance for other approaches of gene therapy using novel types of stem cells. Seminal work by Fischer and Cavazzana-Calvo ( 8) in Paris as well as Thrasher and Gaspar ( 9) in London for X-linked SCID and Bordignon and Aiuti ( 10, 11, 12) in Milan for ADA-SCID, has shown the clinical efficacy of gene therapy for various types of SCID using gene-corrected autologous stem cells. However, delayed immune recovery and the risk of graft-vs.-host disease remain substantial problems that warrant gene repair via gene therapy with autologous cells as an alternative. These issues have mainly been worked out in children with leukemia, for whom suitable donors can often be found, using one of the parents, if necessary. It should be noted, however, that also for SCID, haploidentical stem cell transplantation has become a valuable option for patients lacking a human leukocyte antigen–identical donor ( 7). An alternative to allogeneic stem cells is genetically modified autologous stem cells in which the genetic defect is functionally corrected (i.e., by gene therapy).
However, this treatment is complicated by adverse immune reactions of the donor cells, a slow immune reconstitution, and a lack of suitable donors for most patients.
Replacing the affected bone marrow with allogeneic healthy (stem) cells is currently the only established therapy for SCID. As a consequence, RAG-SCID patients lack B and T cells and develop many serious, life-threatening infections, especially pneumonia, meningitis, and sepsis, as neonates. These patients have mutations in RAG1 or RAG2, which are required for the assembly of the T-cell receptor and B-cell receptor ( 4, 5, 6). The second or third most common form of SCID (depending on the genetic background of the population) is RAG-negative SCID. Mutations in the ADA gene allow the buildup of deoxyadenosine to levels that are toxic to lymphocytes, in particular immature thymocytes. ADA converts deoxyadenosine into nontoxic deoxyinosine.
The ADA enzyme is found throughout the body but is most active in lymphocytes. ADA-SCID patients fail to make T cells, B cells, and NK cells, experience recurrent infections, and fail to thrive ( 3). For many types of SCID, the underlying molecular defect is unknown. Other forms of SCID are those with underlying deficiencies in the adenosine deaminase ( ADA) gene, recombinase-activating genes ( RAG), Artemis, or more rarely in the CD3 genes, ZAP70 and IL7R ( Figure 1). Although B cells are present, their function is severely impaired, not only because of a lack of T-cell help but also because of intrinsic B-cell defects. The incidence is estimated to be roughly 1 in 65,000 live births ( 2) The lymphocytes of patients with X-linked SCID cannot respond to the several essential cytokines (interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21) needed for these cells to develop, survive, and fight infections. Worldwide, the most common form of SCID is X-linked SCID, caused by mutations in the gene coding for the Il2Rγ chain, resulting in SCID with a T −B +NK − phenotype, referring to the lack of T lymphocytes and NK cells, but the presence of B lymphocytes in these patients. The diagnosis is established by detecting lymphopenia, absence or very low numbers of T lymphocytes, and impaired T-cell proliferative responses to mitogens.Ī number of genetic abnormalities can cause SCID. Most infants develop opportunistic infections within the first 6 mo of life. Severe combined immunodeficiency (SCID) is a heterogeneous disease characterized by lack of T lymphocytes and sometimes also B and/or natural killer (NK) cells ( 1). Immunodeficiencies invariably refer to defects in the immune system that lead to an increased risk of infections.
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