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Expert Opinion on Biological Therapy Feb 2008Wiskott Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency. This complex disease is characterised by microthrombocytopenia, recurrent infections, eczema... (Review)
Review
BACKGROUND
Wiskott Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency. This complex disease is characterised by microthrombocytopenia, recurrent infections, eczema and is associated with a high incidence of autoimmunity and of lymphoid malignancies. WAS is attracting growing attention not only because it highlights the rich cellular and systems biology revolving around cytoskeletal regulation but also because it is candidate for a haematopoietic stem cell gene therapy indication.
OBJECTIVES
As several groups are developing this novel approach, this review discusses the state of the art and challenges in clinical development of gene therapy for WAS, with particular regard to biosafety.
METHODS
In spite of the successes of haematopoietic gene therapy for genetic immune deficiencies, there is a need for more efficient transduction protocols and for vectors with a superior safety profile. Preclinical studies have provided reasonable expectations that haematopoietic gene therapy with a self-inactivated HIV-1-derived vector using the native gene promoter for expression of the WAS transgene will be safe and will lead to the restoration of WAS protein in the haematopoietic and immune system at levels sufficient to provide an improvement in the condition of WAS patients.
CONCLUSIONS
Phase I/II clinical studies will soon be initiated in several European centres to assess the safety and efficacy of this lentiviral vector in WAS patients.
Topics: Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Lentivirus; T-Lymphocytes; Transduction, Genetic; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 18194074
DOI: 10.1517/14712598.8.2.181 -
Frontiers in Immunology 2022Actin is an important cytoskeletal protein involved in signal transduction, cell structure and motility. Actin regulators include actin-monomer-binding proteins,... (Review)
Review
Actin is an important cytoskeletal protein involved in signal transduction, cell structure and motility. Actin regulators include actin-monomer-binding proteins, Wiskott-Aldrich syndrome (WAS) family of proteins, nucleation proteins, actin filament polymerases and severing proteins. This group of proteins regulate the dynamic changes in actin assembly/disassembly, thus playing an important role in cell motility, intracellular transport, cell division and other basic cellular activities. Lymphocytes are important components of the human immune system, consisting of T-lymphocytes (T cells), B-lymphocytes (B cells) and natural killer cells (NK cells). Lymphocytes are indispensable for both innate and adaptive immunity and cannot function normally without various actin regulators. In this review, we first briefly introduce the structure and fundamental functions of a variety of well-known and newly discovered actin regulators, then we highlight the role of actin regulators in T cell, B cell and NK cell, and finally provide a landscape of various diseases associated with them. This review provides new directions in exploring actin regulators and promotes more precise and effective treatments for related diseases.
Topics: Actin Cytoskeleton; Actins; Humans; Microfilament Proteins; T-Lymphocytes; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 35371070
DOI: 10.3389/fimmu.2022.799309 -
Blood Dec 2004The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive immune deficiency disorder characterized by thrombocytopenia, small platelet size, eczema, recurrent...
The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive immune deficiency disorder characterized by thrombocytopenia, small platelet size, eczema, recurrent infections, and increased risk of autoimmune disorders and malignancies. X-linked thrombocytopenia (XLT) is an allelic variant of WAS which presents with a milder phenotype, generally limited to thrombocytopenia. WAS and XLT are caused by mutations of the Wiskott-Aldrich syndrome protein (WASP) gene which encodes a 502-amino acid protein, named WASP. WASP is thought to play a role in actin cytoskeleton organization and cell signaling. Here, we report the identification of 141 unique mutations, 71 not previously reported, from 227 WAS/XLT families with a total of 262 affected members. When possible we studied the effects of these mutations on transcription, RNA splicing, and protein expression. By analyzing a large number of patients with WAS/XLT at the molecular level we identified 5 mutational hotspots in the WASP gene and have been able to establish a strong association between genotype and phenotype.
Topics: Child; Child, Preschool; Female; Gene Expression Regulation; Genotype; Humans; Infant; Male; Mutation; Phenotype; Protein Biosynthesis; Proteins; Sequence Deletion; Transcription, Genetic; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 15284122
DOI: 10.1182/blood-2003-05-1592 -
The Journal of Allergy and Clinical... Feb 2013
Topics: Adolescent; Adult; Case-Control Studies; Child; Child, Preschool; Cohort Studies; Female; Galactose; Genetic Diseases, X-Linked; Glomerulonephritis; Glycosylation; Humans; Immunoglobulin A; Infant; Male; Retrospective Studies; Thrombocytopenia; Wiskott-Aldrich Syndrome; Young Adult
PubMed: 23107152
DOI: 10.1016/j.jaci.2012.08.040 -
Biology of Blood and Marrow... Mar 2018Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by a triad of immunodeficiency, eczema, and thrombocytopenia. Currently, hematopoietic stem cell... (Clinical Trial)
Clinical Trial
Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by a triad of immunodeficiency, eczema, and thrombocytopenia. Currently, hematopoietic stem cell transplantation (HSCT) is the most reliable curative treatment with excellent results for patients with HLA-matched family or unrelated donors. However, even after fully myeloablative preparative regimens, mixed donor chimerism is a potential concern. We performed a retrospective chart review of 12 children who underwent allogeneic HSCT for WAS to report our experience. The median age at transplant was 10.5 months (range, 3 to 39). The median nucleated cell dose from the marrow was 4.55 × 10/kg (range, .3 to 7.9). The median times to neutrophil and platelet engraftment were 19 days (range, 13 to 27) and 18.5 days (range, 12 to 31), respectively. The rate of overall survival was 92% with median follow-up of 67 months (range, 3 to 146). Two patients developed grade IV acute graft-versus-host disease, and 1 died on day +99. Five of 12 patient's (42%) had mixed donor chimerism (range, 12% to 85%) at day +180. None of the pretransplant patient parameters was predictive of mixed chimerism. Nonetheless, of these 5 patients, 2 had normalization of the platelet count despite the mixed chimerism, 2 had full donor chimerism after receiving a second transplant with the same donor, and 1 remains transfusion dependent awaiting a second transplant. Hence, even with a significant rate of mixed chimerism, HSCT provides substantial benefit to WAS patients, with excellent overall survival.
Topics: Adolescent; Adult; Allografts; Child; Child, Preschool; Disease-Free Survival; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Male; Retrospective Studies; Risk Factors; Survival Rate; Transplantation Conditioning; Wiskott-Aldrich Syndrome
PubMed: 29196075
DOI: 10.1016/j.bbmt.2017.11.019 -
Molecular Therapy : the Journal of the... Jun 2009Wiskott-Aldrich Syndrome (WAS) is a life-threatening X-linked disease characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancies. Gene therapy...
Wiskott-Aldrich Syndrome (WAS) is a life-threatening X-linked disease characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancies. Gene therapy could represent a therapeutic option for patients lacking a suitable bone marrow (BM) donor. In this study, we analyzed the long-term outcome of WAS gene therapy mediated by a clinically compatible lentiviral vector (LV) in a large cohort of was(null) mice. We demonstrated stable and full donor engraftment and Wiskott-Aldrich Syndrome protein (WASP) expression in various hematopoietic lineages, up to 12 months after gene therapy. Importantly, we observed a selective advantage for T and B lymphocytes expressing transgenic WASP. T-cell receptor (TCR)-driven T-cell activation, as well as B-cell's ability to migrate in response to CXCL13, was fully restored. Safety was evaluated throughout the long-term follow-up of primary and secondary recipients of WAS gene therapy. WAS gene therapy did not affect the lifespan of treated animals. Both hematopoietic and nonhematopoietic tumors arose, but we excluded the association with gene therapy in all cases. Demonstration of long-term efficacy and safety of WAS gene therapy mediated by a clinically applicable LV is a key step toward the implementation of a gene therapy clinical trial for WAS.
Topics: Animals; B-Lymphocytes; Blotting, Western; Female; Genetic Therapy; Immunophenotyping; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Polymerase Chain Reaction; T-Lymphocytes; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 19259069
DOI: 10.1038/mt.2009.31 -
The Journal of Allergy and Clinical... Nov 2015Using a protein microarray, a broad spectrum of autoantibodies were demonstrated in patients with either Wiskott-Aldrich syndrome (WAS) or with X-linked thrombocytopenia...
Using a protein microarray, a broad spectrum of autoantibodies were demonstrated in patients with either Wiskott-Aldrich syndrome (WAS) or with X-linked thrombocytopenia (XLT), indicating that immune dysregulation is an integral component of both diseases.
Topics: Adolescent; Adult; Antibody Diversity; Autoantibodies; Autoantigens; Child; Child, Preschool; Epitopes; Female; Genetic Diseases, X-Linked; Humans; Infant; Male; Middle Aged; Quality of Life; Thrombocytopenia; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein Family; Young Adult
PubMed: 26409660
DOI: 10.1016/j.jaci.2015.08.010 -
Blood Feb 2005The Wiskott-Aldrich syndrome protein (WASp) is mutated in the severe immunodeficiency disease Wiskott-Aldrich syndrome (WAS). The function of B cells and the physiologic...
The Wiskott-Aldrich syndrome protein (WASp) is mutated in the severe immunodeficiency disease Wiskott-Aldrich syndrome (WAS). The function of B cells and the physiologic alterations in WAS remain unclear. We show that B cells from WAS patients exhibited decreased motility and had reduced capacity to migrate, adhere homotypically, and form long protrusions after in vitro culture. WASp-deficient murine B cells also migrated less well to chemokines. Upon antigen challenge, WASp-deficient mice mounted a reduced and delayed humoral immune response to both T-cell-dependent and -independent antigens. This was at least in part due to deficient migration and homing of B cells. In addition, the germinal center reaction was reduced in WASp-deficient mice. Thus, WASp is crucial for optimal B-cell responses and plays a pivotal role in the primary humoral immune response.
Topics: Animals; B-Lymphocytes; Cell Adhesion; Cell Aggregation; Cell Movement; Flow Cytometry; Humans; Mice; Mice, Knockout; Phenotype; Proteins; Spleen; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 15383456
DOI: 10.1182/blood-2004-03-1003 -
Cellular and Molecular Life Sciences :... Jan 2012Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease are chronic and relapsing conditions, characterized by abdominal pain, diarrhea,... (Review)
Review
Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease are chronic and relapsing conditions, characterized by abdominal pain, diarrhea, bleeding and malabsorption. IBD has been considered a hyperinflammatory state due to disturbed interactions between the immune system and the commensal bacterial flora of the gut. However, there is evidence that Crohn's disease might be the consequence of a reduced release of pro-inflammatory cytokines and an impaired acute inflammatory response, thereby suggesting that IBD might be an immunodeficiency rather than an excessive inflammatory reaction. This theory has been supported by observations in patients with primary immunodeficiencies such as the Wiskott-Aldrich syndrome and IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome). In contrary, defects in the anti-inflammatory down-regulation of the immune response as they are seen in patients with Mendelian defects in the IL10 signaling pathway support the hyper-inflammatory theory. In this review, we describe and discuss primary immunodeficiencies associated with IBD and show that the bowel is a highly sensitive indicator of dysregulations, making IBD a model disease to study and identify key regulators required to balance the human mucosal immune system.
Topics: Colitis, Ulcerative; Crohn Disease; Genes, X-Linked; Granulomatous Disease, Chronic; Humans; Interleukin-10; Intestinal Mucosa; Receptors, Interleukin-10; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein; X-Linked Combined Immunodeficiency Diseases
PubMed: 21997382
DOI: 10.1007/s00018-011-0837-9 -
The Journal of Clinical Investigation Nov 1971The Wiskott-Aldrich syndrome is an immune deficiency disorder with an impairment of both humoral and cellular immune responses. Metabolic turnover studies of IgG, IgA,...
The Wiskott-Aldrich syndrome is an immune deficiency disorder with an impairment of both humoral and cellular immune responses. Metabolic turnover studies of IgG, IgA, IgM, and albumin were conducted in seven patients with the Wiskott-Aldrich syndrome using purified radioiodinated proteins. The survival of each of the proteins studied was significantly shortened with a half-time of 7.5 days for IgG (normal 22.9 +/-4 SD), 3.0 days for IgA (normal 5.8 +/-1), 5.0 days for IgM (normal 10.1 +/-2.1), and 8.6 days for albumin (normal 17, range 13-20); the fractional catabolic rates were correspondingly elevated and the distribution of protein among the body compartments was normal. For three of the four proteins. IgG, IgA, and albumin, the steady-state synthetic rates were generally elevated leading to normal or even elevated serum proteins levels. Thus, in the case of IgA, the synthetic rate averaged five times normal while the fractional degradative rate was twice normal. The resulting serum concentration was, therefore, significantly elevated, IgM represented an exception to this pattern in that the increased rate of degradation was not counterbalanced by an increased synthetic rate and, therefore, the serum levels were low. Albumin clearance studies using albumin-(51)Cr showed gastrointestinal protein loss in these patients to be slightly greater than normal, but this could account for only a small fraction of the hypercatabolism observed. There was no proteinuria or abnormalities of thyroid, adrenal, renal, or liver function. Thus, none of the previously recognized causes of increased serum protein catabolism were present. Patients with the Wiskott-Aldrich syndrome, therefore, have a unique disorder of serum protein metabolism characterized by endogenous hypercatabolism of at least four major serum proteins. This phenomenon may be related to reticuloendothelial hyperfunction since the Wiskott-Aldrich syndrome is associated with reticuloendothelial hyperplasia and accelerated clearance of colloidal materials from the plasma.
Topics: Adolescent; Child; Child, Preschool; Chromium Isotopes; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulins; Immunologic Deficiency Syndromes; Infant; Lymphatic Diseases; Male; Metabolic Clearance Rate; Mononuclear Phagocyte System; Protein-Losing Enteropathies; Serum Albumin; Wiskott-Aldrich Syndrome
PubMed: 5096517
DOI: 10.1172/JCI106731