Immune System and Gene Therapy
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
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
Cited: Ashcroft, Richard E.. "Gene Therapy in the Clinic: Whose Risks?" Trends in Biotechnology 22 (2004): 560-563. "Bone Marrow Transplant." Hematology and Blood Disorders. 2007. Lucile Packard Children 's Hospital Cavazzana-Calvo, Maria, et al. "Gene Therapy of Severe Combined Immunodeficiency." The Journal of Gene Medicine 3 (2001): 201-206. Chinen, Javier and Jennifer M. Puck. "Successes and Risks of Gene Therapy in Primary Immunodeficiencies." Journal of Allergy and Clinical Immunology 113 (2004): 595-603. Eun-Kyeong , Jo, et al. "X-linked Severe Combined Immunodeficiency Syndrome: The First Korean Case with γc Chain Gene Mutation and Subsequent Genetic Counseling." Journal of Korean Medical Sciences 19 (2004): 123-126. Griffiths, Anthony J. F., et al. Introduction to Genetic Analysis. 9th ed. New York: W. H. Freeman and Company, 2008. Kohn, B., and Sadelain Michel, and Joseph C. Glorioso. "Occurence of Leukaemia Following Gene Therapy of X-linked SCID." Nature 3 (2003): 477-488. Kohn, D. B.. "Gene Therapy for Genetic Haematological Disorders and Immunodeficiencies." Journal of Internal Medicine 249 (2001): 379-390. Otsu, Markoto and Fabio Candotti. "Gene Therapy in Infants with Severe Combined Immunodeficiency." BioDrugs 16 (2002): 229-239. Strauss, B.E. and E. Constranzi-Strauss. "Combating Oncogene Activation Associated with Retrovirous-mediated Gene Therapy of X-linked Severe Combined Immunodeficiency." Brazilian Journal of Medical and Biological Research 40 (2007): 601-613.