Scid

Severe combined immunodeficiency (SCID) is a rare fatal disorder that occurs in approximately 1 in 75,000 children, usually leading to infant death within one year from birth (Cavazzana-Calvo, et al. pg 202). Patients suffering from SCID have genetic mutations that prevent their immune system from properly developing and functioning, which leads to recurrent and eventually lethal infections. (Kohn, Michel, and Glorioso pg 479)

Most of these patients are diagnosed with a type of SCID called X-linked SCID, which is responsible for about 45% of all SCID cases (Otsu and Candotti pg 233). Allogeneic Bone Marrow transplant (BMT) has been the most commonly used treatment for X-linked SCID patients. However, I believe gene therapy should become the main course of treatment because of the several complications involved with allogeneic BMT and the recent achievements in the development of gene therapy for X-linked SCID.

As the name X-linked SCID suggests, this type of primary immunodeficiency is inherited through an X-linkage pattern, meaning that the mutant gene that is responsible for this disorder is located in the X chromosome but not in the Y. Since SCID is also considered a recessive disorder, it is usually inherited from carrier mothers, unaffected females that contain one normal and one mutated copy of the gene. The son of a carrier has a 50 percent chance of inheriting the disorder while the daughter needs two mutant X chromosomes, thus the father would have to be affected and somehow have survived long enough in order to reproduce and pass on his mutated copy of the gene. Consequently, males tend to be affected by X-linked SCID much more frequently than females. (Griffiths, et al. pg 63, 64, 71, 72)

X-linked SCID is caused by a mutation in the IL2RG gene that encodes the Y-common chain. Many cytokine receptors (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21), receptors that influence and regulate cell behavior, utilize this Y-common chain for signal transduction. In particular, the unsuccessful signaling of IL-7 and IL-15 inhibits the proper development of T and natural killer (NK) lymphocyte cells respectively, and therefore significantly hinders the immune system. (Cavazzana-Calvo, et al. pg 203)

Although X-linked SCID patients lack T and NK cells, B cells tend to be present in normal or often high numbers, however these cells are not functional (Otsu and Candotti pg 233). This lack and inefficiency of T, NK, and B immune cells gives the patient no chance to fight off infections. Even small infections such as a cold can lead to the death of an untreated X-linked SCID patient. Other symptoms afflicting these patients include the lack of tonsils, a small thymus, and absence of lymph nodes. (Eun-Kyeong, et al. pg 123)

Gene therapy provides an efficient approach to repairing a patient's immune system. This treatment involves placing a fully functioning version of the mutated gene in the patient's body in order to surpass the genetic deficiency created due to this mutated gene. Allogeneic BMT could be circumvented if successful gene therapy is accomplished through an efficient gene delivery into haematopoietic stem cells (HSC), parent cells that develop into all other blood cell types. Successful gene delivery is achieved through the use of retroviral vectors, survival of the gene throughout cell growth, and sufficient gene expression. (Kohn pg 379, Human Genome Project Information, Gene Therapy)

X-linked SCID is regarded as a great candidate for gene therapy because the disorder is caused by mutations in one single gene (monogenic vs. polygenic) whose function has already been identified (Chinen and Puck pg 596). However gene therapy treatment is not yet fully developed and therefore its success potential can be limited. As a result, there is a major controversy on whether this treatment should be approved at this time or if studies should be prolonged before any premature testing in humans occurs.

Although gene therapy is not a guaranteed success I believe it should be chosen as the main treatment for X-linked SCID instead of BMT. In BMT, HSCs are retrieved from an appropriate donor, often a HLA-matched sibling or HLA-haploidentical donor, usually a parent or sibling who is genetically similar to the patient (Lucile Packard Children's Hospital, Bone Marrow Transplant). These acquired HSC cells are then implanted into the patient to provide them with successful development of functioning white blood cells. (Otsu and Candotti pg 230)

If a HLA-identical donor, a person who has the same genetic make up as the patient, is found the success rate of a BMT is 90 percent. However, finding these donors is very difficult and unlikely. Therefore most BMTs are done with HLA-haploidentical donors, which decreases survival rates to as low as 40 percent and introduces many new complications (Strauss and Constranzi-Strauss pg 603, Ashcroft pg 560, Kohn, Michel and Glorioso pg 479, Ped-Onc Resource Center, Bone Marrow/Stem Cell Transplants). According to "Bone Marrow Transplant" by Lucile Packard Children's Hospital, patients many times experience graft failure due to infections or the lack of sufficient number of stem cells being implemented in the body and in this case the patient needs to undergo another BMT procedure.

Patients who receive non-matched BMT are also under the risk of having graft versus host disease (GVHD). GVHD occurs because the immune cells from the transplanted bone marrow perceive the body of the patient as a foreign entity. This causes them to attack the organs, often leading to the patient's death. Graft rejection is also possible, meaning the patient's body is the one who attacks the new implanted immune cells. This results in the rejection of the donated marrow and requires another attempt at a BMT transplant. (Otsu and Candotti pg 231, Chinen and Puck pg 597)

In addition to all the possible complications that can be sprung up by an inefficient allogeneic BMT, Chinen and Puck state that even if the BMT is successful there is still a chance that the patient will only receive limited recovery and reconstitution of their T and B cells (pg 600). Although having partly operating immune cells is better than having none at all, which is the case of a patient suffering from SCID; it certainly does not guarantee that life-threatening infections will cease from taking place regularly. Consequently, I think selecting gene therapy to correct the disorder by creating a lifelong self renewal supply of fully functioning white blood cells, while also avoiding all BMT complications, is certainly worth the try.

Successful gene therapy also frees patients from the need of having constant antibiotic treatment and intravenous immunoglobulin (IVIG) replacement. Antibiotics and IVIG are used to prevent recurrent contaminations such as upper respiratory