Inherited Immunodeficiencies

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 page describes congenital diseases that are caused by a mutation in any one of several hundreds of genes essential to the development of a fully active immune response. Although congenital immunodeficiency was initially treated by transplantation of allogeneic hematopoietic stem cells, studies over the past 30 years have shown that these conditions are correctable by gene therapy (Thrasher, A.J. and Williams D.A. (2017) Mol.Ther. 25:1132).

Gene therapy strategies that insert a normal copy of the defective gene into the patient’s own hematopoietic stem cells have been tested in different forms of SCID. The motivation for developing gene therapy for primary immunodeficiency’s was that it would bypass the need for a suitable transplant donor, avoid the burden of Graft versus Host Disease and the toxicities associated with pre-transplant conditioning. While initial clinical trials were only partially effective and indicated serious safety issues, recent progresses in the design of retroviral and lentiviral vectors as well as improvements in hematopoietic stem cell transplantation are now making gene therapy a likely standard of care for some of these diseases.

Adenosine Deaminase Deficient-SCID: Mutations or deletions in the adenosine deaminase (ADA) gene cause adenosine deaminase-severe combined immunodeficiency (ADA-SCID), commonly know as bubble boy disease. ADA-SCID patients fail to make T cells, B cells and NK (Natural Killer) cells, experience recurrent infections and fail to thrive. Regular infusions of polyethylene-glycol-conjugated ADA (PEG-ADA) can partially rescue the immune system. Over eighty ADA-SCID patients have now 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 PEG-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 70% of them have not needed PEG-ADA infusions. Notably, one of the first-generation retroviral vectors has now been successfully developed into a commercial product (Strimvelis), through a collaboration between Glaxo Smith Kline and Ospedale San Raffaele in Milan. Improved vectors, based on lentivirus, are currently in clinical trials. Over 30 patients have now been treated with these vectors and preliminary data indicate excellent efficacy and safety.

X-linked SCID: Deletions or mutations of the common gamma chain 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. Additionall,y 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 described for ADA-SCID, except they have not required treatment with chemotherapy. A retroviral vector was used to insert a normal gamma chain receptor gene into 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, almost 20 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 effective 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. Based on these advances, nine patients have received an improved retroviral vector in a new clinical study and no severe adverse event has been reported in a five-year follow-up. A more recent study on five older patients having failed hematopoietic stem cell transplantation, has used a lentiviral vector and low dose conditioning. A good response to therapy was observed with this advanced protocol.  

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 to produce 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 so this form of CGD affects males. In clinical trials, hematopoietic stem cells from a total of 12 CGD patients were treated with a retroviral vector to insert the normal gp91phox and then were transferred back into the 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, as a result of gene therapy, these patients could fight off pre-existing 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, a condition called myelodysplasia. Another pitfall was the observation that the production of gp91phox was progressively shut off in the patient’s cells, due to an epigenetic modification of the vector DNA sequences. New lentiviral vectors have subsequently been developed that maintain long term expression of the gp91phox gene and have an improved safety profile. Preliminary data in patients treated with this improved gene therapy are very encouraging, with sustained correction and an absence of insertional mutagenesis.

Wiskott-Aldrich Syndrome: The gene mutated in Wiskott-Aldrich Syndrome (WAS) is a key protein that regulates the shape and function of several types of blood cells. The defects in WAS affect platelet numbers and size, the activity of several types of white blood cells and antibody production. Patients with severe WAS have low platelet counts (which may lead to severe bleeding), eczema, and immunodeficiency. They are highly susceptible to infections and autoimmune disorders. The first gene therapy clinical trial for WAS was conducted on 10 patients whose HSC’s were treated with a first-generation retroviral vector and who received a low dose of busulfan conditioning. While improvements were obvious in 9 out of the 10 patients, most of developed leukemia’s associated to insertional mutagenesis. As with other SCID’s new vector design and HSC transplantation protocols were then implemented in a second series of trials involving over 20 patients. Clear improvements in safety and efficacy have been reported.

There are more than 300 genes associated with Primary Immunodeficiency’s and gene therapy approaches are being developed for many of them. Beyond the classical gene replacement paradigm used so far, molecular interventions such as gene editing or RNA silencing are now available. They will eventually allow more precision and safety and may be used to address a wider range of diseases due to dominant mutations. It is likely that the remarkable –but still unfolding– success of gene therapy for the indications discussed above will result in a platform approach that will be able to address many other diseases. Thirty year of efforts have resulted in robust gene transfer technologies and significant progresses in procedures for isolation, manipulation ex vivo and re-implantation of hematopoietic stem cells. Gene therapy is now poised to become the new standard of care for many of these severe and often intractable diseases.

Please consult your physician before making any medical decisions.

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