X-linked Severe Combined Immunodeficiency (X-linked SCID) is the most common form of Severe Combined Immunodeficiency; a disorder of the immune system where the body produces very few T cells and Natural Killer (NK) cells. X-linked SCID patients are unable to mount effective antibody responses to antigens they may come into contact with.
X-linked SCID is an extremely life-altering disease, which has in the past confined some patients to living in a sterile “bubble,” to avoid contact with pathogens which they would be unable to fight off. This was famously demonstrated by the life of David Vetter, an X-linked SCID sufferer who lived in a sterile chamber – coined by the media as his “bubble” – for all his life. He died in 1984 at age 12 following a bone marrow transplant.
The disease is caused by a recessive mutation, and occurs almost exclusively in males because they have only one X-chromosome. Females have two X-chromosomes, and are very unlikely to have the defective gene on both. The mutation is in a gene called IL2RG, which encodes the “common gamma chain” (γc), a component of many cytokine receptors; IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.
As the γc chain is required for a number of cytokine receptors, patients with X-linked SCID have defective cytokine signalling. IL-7 (and therefore the IL-7 receptor) and IL-15 (and therefore the IL-15 receptor) are essential for early T lymphocyte and Natural Killer cell development, respectively. Consequently, T and NK cells are profoundly defective, and sufferers cannot mount antibody responses (which are dependent on T cells) or cell-mediated immunity such as cytotoxic T cell killing. As a result, X-linked SCID sufferers are highly susceptible to pathogens, and commonly die in early childhood without treatment.
For most SCID patients, bone marrow transplants are the optimal treatment for the disease. This allows the patient’s abnormal immune cells to be replaced with healthy cells from the bone marrow donation. Ideal donors are HLA (Human Leukocyte Antigen)-identical relations such as a sibling, but it is possible to obtain a bone marrow transplant from a parent or HLA-matched unrelated donor. Although bone marrow transplantation can be a successful treatment for X-linked SCID, there is a serious risk of developing Graft-versus-Host Disease (GVHD), a complication which can be fatal. Additionally, many patients do not have a suitable HLA-identical relation such as a sibling. Due to lower success rates of using non-HLA-identical bone marrow donors, bone marrow transplantation is not always a preferable treatment. In recent years, gene therapy as a treatment for X-linked SCID has been extensively researched and trialled, as an alternative to bone marrow transplants.
A clinical trial which began in Paris in 1999 illustrates the conflicting risks and benefits of gene therapy as a treatment for X-linked SCID. 10 infants with the disease took part in the study, where normal human γc chain cDNA was transferred into their bone marrow CD34+ cells using a retroviral vector (Cavazzana-Calvo et al, 2000). Initially, the results of the gene therapy were good, with the infants expressing the normal IL2RG gene in T, NK and B cells, and therefore producing the functional γc chain protein. However, over the following 5 years, four of the clinical trial patients developed a T cell leukaemia-like complication, which led to the death of one of the patients. During the gene therapy procedure, the retroviral vector was integrated near the first exon of the LMO2 gene. LMO2 encodes a protein involved in stem cell growth, which is not normally activated in T cells. Its inappropriate activation can cause spontaneous cases of T cell leukaemia; it is thought that the retroviral vector inserting the normal IL2RG gene may have “turned on” the LMO2 oncogene during its integration into the chromosome. This caused overexpression of the oncogene and lead to the leukaemia cases
The relative benefits and risks of both bone marrow transplantation and gene therapy have to be considered in order to determine the best treatment option for individual X-linked SCID patients. Gene therapy is now known to carry previously unforeseen risks such as the possibility of T cell leukaemia development. However, it has been shown to provide sustained clinical benefit to the majority of patients. Bone marrow transplantation is a more established treatment option, but carries risks of serious complications such as GVHD, as well as problems associated with many patients not having access to a HLA-identical donor. Treatment choice is dependent on a number of factors; access to identical bone marrow donors, as well as weighing up the associated risks of both bone marrow transplants and gene therapy. With X-linked SCID, patients do not live beyond childhood unless treated, so it is important to initiate therapy at a young age.