Immunodeficiency is a defect in the immune system that prevents immune resistance to infectious disease and some forms of cancer. There are two types of immunodeficiency: the primary or congenital form, caused by genetic defect in one of several essential genes involved in maturation of the immune response; and the acquired or secondary immunodeficiency caused by chemotherapy, some forms of cancer or chronic infections such as AIDS. This section describes congenital diseases that are caused by a mutation in any one of several genes essential to the development of a fully active immune response. Although congenital immunodeficiency was initially treated by transplantation of allogeneic hematopoietic stem cells, the past 20 years has shown that these conditions are correctable by gene therapy (link Nature Immunology 11, 457–460 (2010).
One noted patient with severe combined immune deficiency (SCID) lived in an enclosed room for several years to protect him against infection and therefore this disease has been nicknamed “Bubble Baby Disease.” The current treatment of choice for immunodeficiency diseases is the transplantation of bone marrow or hematopoietic stem cells from matched siblings. However, many patients do not have a matched sibling who can serve as a donor. One type of SCID is caused by the lack a protein (adenosine deaminase or ADA-SCID) which has been treated by periodic administration of missing ADA enzyme that results in clinical improvement, but requires an expensive lifelong treatment. Gene-cell therapy strategies that insert a normal copy of the defective gene for ADA into the patient’s own hematopoietic stem cells are being tested as effective treatment in different forms of SCID. Fig. 1 (add the fig) displays the basic steps involved in the development of gene and cell therapy for the immunodeficiency disease called ADA-SCID. The current status of gene and cell therapy for the immunodeficiency diseases treated to date is summarized below.
ADA-SCID: A mutation or deletion in the adenosine deaminase (ADA) gene can cause adenosine deaminase-severe combined immunodeficiency (ADA-SCID). ADA-SCID patients fail to make T cells, B cells and NK (Natural Killer) cells, experience recurrent infections and fail to thrive. At least thirty ADA-SCID patients have been treated with gene and cell therapy in one of several clinical trials. Although the first trials detected gene corrected T cells in the patients, the number of “corrected” and functional T cell levels were low. The experimental approach was improved by pre-treating the patients with a low dosage of busulfan, a chemotherapy drug which facilitated the engraftment of the ADA-corrected hematopoietic stem cells in the bone marrow. Without ADA enzyme therapy being given, the ADA corrected cells had a survival advantage over the patients’ original cells. The transplanted gene modified stem cells provided gene corrected lymphocytes that populated 1-10% of the blood in most patients. Most patients treated in recent years have remained well and have not needed ADA replacement enzyme therapy. Improved vectors, based on lentiviral vectors, are currently in development. According to clinicaltrials.gov, several clinical trials are recruiting ADA-SCID patients.
X-linked SCID: Deletions or mutations of the common gamma chain (gc) found in the cell surface receptors for several cytokine (hormones that activate the immune cells) causes X- linked severe combined immunodeficiency (X-linked SCID, also called SCID-X1). The immune cells of patients with X-linked SCID cannot respond to the several essential cytokines (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21) needed for these cells to survive and fight infections. Thus, patients with X-linked SCID lack T cells and NK cells and the functions of their B cells, which make antibodies, are impaired. The basic gene-cell therapy strategy for treatment of X-linked SCID was similar to the approach shown for the ADA-SCID form of disease, except they have not required treatment with chemotherapy. Basically, a retroviral vector carried the normal gamma chain receptor gene into some of the hematopoietic stem cells from the bone marrow of X linked-SCID patients. The cells were transfused back into the patients. Overall, 17 of the 20 patients enrolled in two trials experienced higher, functional T cell and NK numbers. New T cells are still maturing in these patients ten years after the initial gene therapy. This same therapy in older X-linked SCID patients was not as successful, likely because the thymus, which plays an essential role in “educating” T cells during their development, had shrunk and was not reactivated by the therapy. The results suggest that therapy is more efficacious in younger patients. Five patients treated with the first generation retroviral vector based gene therapy developed a leukemia that was related to the treatment. They were treated for this complication and four of the five survived with continued corrections of their immune system. One patient succumbed to the leukemia. However, these unfortunate events have spurred research on understanding the mechanisms of viral induced leukemia, the development of safer vectors, and the improvement of safety standards. New clinical trials are enrolling patients using these advances. http://www.ncbi.nlm.nih.gov/pubmed/20660403
Chronic Granulomatous Disease (CGD): Chronic Granulomatous Disease is caused by the inability of white blood cells to kill invading fungi and bacteria, because they lack a normal gene needed for the production of the germ-killing superoxide and toxic oxygen metabolites. A defect in the gp91phox gene occurs in approximately 70% of CGD patients. The gp91phox gene is located on the X chromosome and so this form of CGD affects males. In clinical trials, hematopoietic stem cells (HSC) from CGD patients were treated with gene therapy to insert the normal gp91phox and then were transferred back into the CGD patients. As for the ADA-SCID patients, low dose busulfan, which facilitates the engraftment of gene-modified HSC, was given to improve the efficacy. Remarkably, these patients were able to fight off serious infections that had been resistant to all forms of medical management, including new generations of antibiotics. However, two patients developed abnormalities in their bone marrow resulting in the underproduction of a class of blood cells, a condition called myelodysplasia. New gene transfer vectors have been developed that maintain long term expression of the gp91phox gene and have an improved safety profile in this type of cells.
Wiskott-Aldrich Syndrome: The gene mutated in Wiskott-Aldrich Syndrome codes for WASP, a key protein that regulates the shape and function of several types of blood cells. The defects in WASP affect platelet numbers and size, the activity of several types of white blood cells and antibody production. Patients with severe Wiskott-Aldrich Syndrome have low platelet counts (which may lead to severe bleeding), eczema, and immunodeficiency. They are highly susceptible to infections and autoimmune disorders. Clinical trials of gene therapy for Wiskott-Aldrich syndrome have been initiated recently, and this therapy appears to be effective in correcting the function of immune cells. In summary, gene-cell therapy protocols have shown promise in treatment of patients with immunodeficiency diseases. Challenges imposed by complications that occurred in trials in CGD and X linked SCID have been met with the development of improved vectors that have been shown to be safer in pre-clinical studies. Ongoing clinical trials hope to provide effective and safe treatments for more children.
For more information on inherited immune deficiencies, please visit the following organizational and informational websites:
An Article in MedlinePlus
An Article in MedPage Today
Genetic and Rare Diseases Information Center (GARD)
International Patient Organisation for Patients with Primary Immunodeficiencies (IPOPI)
Severe Combined Immunodeficiency
Please consult your physician before making any medical decisions.