Current understanding of the Wiskott–Aldrich syndrome and prospects for gene therapy
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Gene therapy, based on the transplantation of genetically corrected autologous hematopoietic stem cells (HSCs), has proven to be an effective therapeutic approach as an alternative to allogenic HSC transplantation for the cure of severe combined immunodeficiencies (SCID). In this article, the recent preclinical studies aiming towards gene therapy trials for the Wiskott–Aldrich syndrome (WAS), a life-threatening immunodeficiency characterized by infections, hemorrhages, autoimmune disorders and lymphomas, will be reviewed. An update of the safety and efficacy data obtained in studies performed in murine disease models and in cells from WAS patients will be presented. Based on these data and on the clinical results of the recent trials for SCID, the most critical issues regarding the implementation of a gene therapy approach for WAS will be discussed.Keywords:
Wiskott–Aldrich syndrome
Wiskott–Aldrich syndrome protein
Primary Immunodeficiency
Primary Immunodeficiency
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Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease with unique and characteristic features. In 1994, the responsible gene for WAS, the WASP gene on X-chromosome, was identified. Since then, renewed clinical and basic researches of WAS have started and remarkably developed. I will comment on recent progress in the clinical and basic researches of WAS, including some topics reported by our and other groups.
Primary Immunodeficiency
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Wiskott — Aldrich syndrome (WAS) is a rare, X-linked combined disease with immunodeficiency caused by mutations in the WAS gene that encodes the WAS protein (WASp). Manifestations range from a relatively mild form of the disease (intermittent X-linked thrombocytopenia), characterized by thrombocytopenia with or without minor immunodeficiency, to a severe form with deep immunodeficiency, episodes of bleeding, the development of autoimmunity and an increased risk of malignancy. Many patients have intermediate degrees of severity. It is precisely this heterogeneity in the clinical spectrum that makes it difficult to make a primary diagnosis of WAS. The article presents a clinical case of primary immunodeficiency detected in a 2-month-old child.
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Immunodeficiency Syndrome
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This chapter contains sections titled: Introduction Severe combined immunodeficiency syndrome HCT for SCID Wiskott-Aldrich syndrome Gene therapy for SCID and other lethal disorders of immunity X-linked γc-deficient SCID Other lethal immunodeficiencies Conclusion References
Wiskott–Aldrich syndrome
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Immunologic Deficiency Syndromes
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Severe combined immunodeficiency (SCID) is the most life-threatening form of primary immunodeficiency, fatal within the first years of life if hematopoietic stem cell transplantation (HSCT) is not performed. Early diagnosis is crucial for prevention of multiple life-threatening complications, which in turn allows for successful HSCT. Current publication contains clinical recommendations for diagnosis of SCID and its complications, complex treatment, including HSCT, prenatal diagnostics and genetic family counselling.
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Abstract Wiskott‐Aldrich syndrome (WAS) also called the eczema‐thrombocytopenia‐immunodeficiency syndrome is a primary immunodeficiency disease with X‐linked recessive inheritance caused by mutations in the WAS protein (WASp) gene and characterized by thrombocytopenia with reduced platelet volume, eczema, immunodeficiency, and increased risk of malignant tumours. The mutations will lead to separate WAS severity which can be typical severe ‘classical’ WAS or less severe ‘non‐classical’ WAS. This article will review and analyse clinical and immune characteristics of five unrelated Chinese families harbouring classical and non‐classical WAS. The expression of WASp was detected in the peripheral blood monocytes (PBMC) by flow cytometry, and five mutations were found by WAS gene sequencing, one of which had not been reported in the literature, namely frameshift mutation c.1240_1247delCCACTCCC (p. P414Sfs*41).
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Abstract Immunodeficiency is a condition caused by a defect in the immune system, leading to a failure to protect the body adequately from infection. It should be considered in anybody with a history of recurrent infections, two or more episodes of life‐threatening infections, infections with unusual or opportunistic organisms or with unexpected or severe complications. Immunodeficiency may be either primary or secondary in origin. Primary immunodeficiency (PID) may present as early as the first 3–4 weeks of life with severe diarrhoea, resulting in failure to thrive, recurrent infections and severe eczema. However, it may also manifest in early childhood or later, depending on the nature of the underlying disease and genetic mutation. It is essential to diagnose PID early, particularly severe combined immune deficiency (SCID), in order to prevent infections and organ damage and offer curative treatment such as haematopoietic stem cell transplantation (HSCT) or gene transfer (GT). Key Concepts Defects in the immune system can put patients at risk of life‐threatening infections. Primary immunodeficiency consists of a wide range of disorders that affect adaptive or innate immunity. Early diagnosis of primary immunodeficiency is essential for successful outcome. The most common manifestation of immunodeficiency is recurrent respiratory infections. The most predictive of 10 warning signs for a diagnosis of PID are family history, need for intravenous antibiotics for sepsis and failure to thrive. Next‐generation sequencing has led to the discovery of novel genetic causes of known and new PIDs. Outcome of haematopoietic stem cell transplantation has greatly improved. Gene therapy is successful and increasingly available for a number of disorders. Secondary immunodeficiency can be caused by infection such as HIV.
Primary Immunodeficiency
Immune Dysregulation
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Common Variable Immunodeficiency
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Primary immunodeficiency syndromes may be seen as "experiments of nature", giving insights into the organization and function of the human immune system. The principal categories of primary immunodeficiency syndromes: severe combined immunodeficiency, agammaglobulinemia and isolated T-cell defects (e.g. Di George Syndrome) are still used in view of their leading clinical presentations. However, detailed analysis of individual cases and families now shows a plethora of different diseases in each category. In this review the relationship of primary immunodeficiency diseases of the B-cell system and autoimmune phenomena are discussed. The pathology of thymus in severe combined immunodeficiency is shown: central maturation defects of the T-cell system are not due to "dysplasia" of the thymus but rather to enzyme defects of the lymphatic cells. Severe alterations of the thymus may also be caused by graft versus host disease. The clarification of genetic defects of lymphoid differentiation and maturation today may lead to improved early and prenatal diagnosis as well as specific gene therapy. The success of bone marrow transplantation in many cases of primary immunodeficiency disease syndromes may be considered as a consequence of successful gene therapy.
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