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Scandinavian Journal of Immunology Jan 2020Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease caused by a mutation in the WAS gene that encodes the WAS protein (WASp); up to 5-10% of...
Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease caused by a mutation in the WAS gene that encodes the WAS protein (WASp); up to 5-10% of these patients develop inflammatory bowel disease (IBD). The mechanisms by which WASp deficiency causes IBD are unclear. Intestinal microbial dysbiosis and imbalances in host immune responses play important roles in the pathogenesis of polygenetic IBD; however, few studies have conducted detailed examination of the microbial alterations and their relationship with IBD in WAS. Here, we collected faecal samples from 19 children (all less than 2 years old) with WAS and samples from WASp-KO mice with IBD and subjected them to 16S ribosomal RNA sequencing. We found that microbial community richness and structure in WAS children were different from those in controls; WAS children revealed reduced microbial community richness and diversity. Relative abundance of Bacteroidetes and Verrucomicrobiain in WAS children was significantly lower, while that of Proteobacteria was markedly higher. WASp-KO mice revealed a significantly decreased abundance of Firmicutes. Faecal microbial dysbiosis caused by WASp deficiency is similar to that observed for polygenetic IBD, suggesting that WASp may play crucial function in microbial homoeostasis and that microbial dysbiosis may contribute to IBD in WAS. These microbial alterations may be useful targets for monitoring and therapeutically managing intestinal inflammation in WAS.
Topics: Animals; Biodiversity; Biomarkers; Case-Control Studies; Child, Preschool; Disease Models, Animal; Dysbiosis; Feces; Female; Gastrointestinal Microbiome; Humans; Infant; Inflammatory Bowel Diseases; Male; Metagenome; Metagenomics; Mice; Mice, Knockout; Mutation; RNA, Ribosomal, 16S; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 31267543
DOI: 10.1111/sji.12805 -
Current Opinion in Allergy and Clinical... Dec 2011Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency (PID) characterized by micro-thrombocytopenia, recurrent infections, eczema, which is... (Review)
Review
BACKGROUND
Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency (PID) characterized by micro-thrombocytopenia, recurrent infections, eczema, which is associated with a high incidence of auto-immunity and lymphoreticular malignancy. One of the first diseases to be successfully treated by allogeneic hematopoietic stem cell transplantation, WAS is currently the subject of several phase I/II gene therapy trials for patients without HLA-compatible donors.
PURPOSE OF REVIEW
This article reviews the preclinical and clinical data leading to the development of gene therapy of WAS with lentiviral vectors.
RECENT FINDINGS
A recent clinical trial using a conventional gammaretroviral vector has demonstrated the proof of principle of gene therapy in WAS, but has also highlighted a common limitation of the technology. Encouraging preclinical efficacy and safety results using refined lentiviral vectors, and the development of robust clinical-grade manufacturing processes have supported the initiation of several phase I/II new studies.
SUMMARY
WAS is amenable to hematopoietic stem cell gene therapy. New trials using lentiviral vectors are expected to improve efficacy and safety profiles. Beyond proof of principle, ongoing international efforts to coordinate trials of gene therapy for the WAS may also provide a model for the expedited development of new treatments for other rare diseases.
Topics: Clinical Trials as Topic; Genetic Therapy; Genetic Vectors; Hematopoietic Stem Cell Transplantation; High-Throughput Screening Assays; Humans; Lentivirus; Thrombocytopenia; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 21971332
DOI: 10.1097/ACI.0b013e32834c230c -
Clinical Infectious Diseases : An... Aug 2023
Topics: Male; Humans; Wiskott-Aldrich Syndrome; Skin; Face
PubMed: 37607355
DOI: 10.1093/cid/ciac955 -
Hematology. American Society of... 2009The Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disease with a characteristic clinical phenotype that includes thrombocytopenia with small platelets,... (Review)
Review
The Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disease with a characteristic clinical phenotype that includes thrombocytopenia with small platelets, eczema, recurrent infections due to immunodeficiency, and an increased incidence of autoimmune manifestations and malignancies. The identification of the molecular defect in the WAS gene has broadened the clinical spectrum of disease to include chronic or intermittent X-linked thrombocytopenia (XLT), a relatively mild form of WAS, and X-linked neutropenia (XLN) due to an arrest of myelopoiesis. The pathophysiological mechanisms relate to defective actin polymerization in hematopoietic cells as a result of deficient or dysregulated activity of the WAS protein (WASp). The severity of disease is variable and somewhat predictable from genotype. Treatment strategies therefore range from conservative through to early definitive intervention by using allogeneic hematopoietic stem cell transplantation and potentially somatic gene therapy. All aspects of the condition from clinical presentation to molecular pathology and basic cellular mechanisms have been reviewed recently.
Topics: Actins; Autoimmune Diseases; Biopolymers; Combined Modality Therapy; Cytoskeleton; Genetic Predisposition to Disease; Genetic Therapy; Genotype; Hematopoietic Stem Cell Transplantation; Humans; Infections; Lymphocyte Subsets; Neoplasms; Neutropenia; Platelet Transfusion; Splenectomy; Thrombocytopenia; Transplantation, Homologous; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 20008191
DOI: 10.1182/asheducation-2009.1.132 -
Immunology and Allergy Clinics of North... May 2010The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by a triad of diagnostic clinical elements: immunodeficiency, eczema, and hemorrhage caused by... (Review)
Review
The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by a triad of diagnostic clinical elements: immunodeficiency, eczema, and hemorrhage caused by thrombocytopenia with small-sized platelets. The formal proof that hematopoietic cell transplantation (HCT) could be used to cure WAS revealed a requirement for both immunosuppression and myelosuppression that still underlies the standard approach to curative therapy today. The current short- and long-term toxicities of HCT are the main stumbling block for the ability to cure every patient with WAS and X-linked thrombocytopenia, and much remains to be done.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; CD40 Antigens; Chemotherapy, Adjuvant; Hematopoietic Stem Cell Transplantation; Histocompatibility; Humans; Immunity, Cellular; Myeloablative Agonists; Rituximab; Stem Cell Niche; Wiskott-Aldrich Syndrome
PubMed: 20493395
DOI: 10.1016/j.iac.2010.02.001 -
Blood Jun 2009Wiskott-Aldrich syndrome (WAS) is a severe X-linked immunodeficiency caused by mutations in the gene encoding for WASP, a key regulator of signaling and cytoskeletal... (Review)
Review
Wiskott-Aldrich syndrome (WAS) is a severe X-linked immunodeficiency caused by mutations in the gene encoding for WASP, a key regulator of signaling and cytoskeletal reorganization in hematopoietic cells. Mutations in WASP result in a wide spectrum of clinical manifestations ranging from the relatively mild X-linked thrombocytopenia to the classic full-blown WAS phenotype characterized by thrombocytopenia, immunodeficiency, eczema, and high susceptibility to developing tumors and autoimmune manifestations. The life expectancy of patients affected by severe WAS is reduced, unless they are successfully cured by bone marrow transplantation from related identical or matched unrelated donors. Because many patients lack a compatible bone marrow donor, the administration of WAS gene-corrected autologous hematopoietic stem cells could represent an alternative therapeutic approach. In the present review, we focus on recent progress in understanding the molecular and cellular mechanisms contributing to the pathophysiology of WAS. Although molecular and cellular studies have extensively analyzed the mechanisms leading to defects in T, B, and dendritic cells, the basis of autoimmunity and thrombocytopenia still remains poorly understood. A full understanding of these mechanisms is still needed to further implement new therapeutic strategies for this peculiar immunodeficiency.
Topics: Adolescent; Animals; Autoimmune Diseases; Child; Dendritic Cells; Eczema; Genetic Predisposition to Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Lymphocyte Subsets; Male; Mice; Neoplastic Syndromes, Hereditary; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein; Young Adult
PubMed: 19351959
DOI: 10.1182/blood-2008-12-115253 -
The New England Journal of Medicine Apr 1980
Topics: Anti-Bacterial Agents; Bone Marrow Transplantation; Child; Humans; Infection Control; Spleen; Splenectomy; Thrombocytopenia; Transplantation, Homologous; Wiskott-Aldrich Syndrome
PubMed: 6767188
DOI: 10.1056/NEJM198004173021610 -
Clinical and Translational Medicine Apr 2022
Topics: Genetic Therapy; Humans; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 35437889
DOI: 10.1002/ctm2.815 -
The Journal of Allergy and Clinical... Mar 2019
Topics: Child; Child, Preschool; Hematopoietic Stem Cell Transplantation; Hemorrhage; Humans; Infant; Platelet Count; Splenectomy; Wiskott-Aldrich Syndrome
PubMed: 30048768
DOI: 10.1016/j.jaip.2018.07.009 -
Immunological Reviews Dec 2000The Wiskott-Aldrich syndrome protein (WASp) is a member of a unique family whose members share similar domain structures and are responsible for the transduction of... (Review)
Review
The Wiskott-Aldrich syndrome protein (WASp) is a member of a unique family whose members share similar domain structures and are responsible for the transduction of signals from the cell membrane to the actin cytoskeleton. For WASp, the interactions with Rho family GTPases and the cytoskeletal organising complex Arp2/3 are critical to these functions, which when disturbed translate into abnormalities of haematopoietic cell signaling, polarisation, migration and phagocytosis. This review discusses the evidence for regulation of highly dynamic cytoskeletal structures by WASp and the consequences of disturbed function on some of these processes.
Topics: Actins; Binding Sites; Cell Adhesion; Cytoskeleton; Female; Genetic Linkage; Hematopoietic System; Humans; Male; Phagocytosis; Phenotype; Protein Structure, Tertiary; Proteins; Signal Transduction; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein; X Chromosome
PubMed: 11213796
DOI: 10.1034/j.1600-065x.2000.17803.x