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British Journal of Haematology May 2019Wiskott Aldrich syndrome (WAS) is a primary immunodeficiency disease resulting in recurrent infections, eczema and microthrombocytopaenia. In its classical form,... (Review)
Review
Wiskott Aldrich syndrome (WAS) is a primary immunodeficiency disease resulting in recurrent infections, eczema and microthrombocytopaenia. In its classical form, significant combined immune deficiency, autoimmune complications and risk of haematological malignancy necessitate early correction with stem cell transplantation or gene therapy. A milder form, X-linked thrombocytopaenia (XLT), shares similar bleeding risk from thrombocytopaenia but is not associated with other significant clinical features and is generally managed conservatively. Here, we detail our approach to the diagnosis and treatment of classical WAS and XLT.
Topics: Autoimmune Diseases; Conservative Treatment; Eczema; Female; Genetic Techniques; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Heterozygote; Humans; Infection Control; Male; Mutation; Risk Factors; Thrombocytopenia; Wiskott-Aldrich Syndrome
PubMed: 30864154
DOI: 10.1111/bjh.15831 -
Nature Communications Jun 2022The diverse functions of WASP, the deficiency of which causes Wiskott-Aldrich syndrome (WAS), remain poorly defined. We generated three isogenic WAS models using patient...
The diverse functions of WASP, the deficiency of which causes Wiskott-Aldrich syndrome (WAS), remain poorly defined. We generated three isogenic WAS models using patient induced pluripotent stem cells and genome editing. These models recapitulated WAS phenotypes and revealed that WASP deficiency causes an upregulation of numerous RNA splicing factors and widespread altered splicing. Loss of WASP binding to splicing factor gene promoters frequently leads to aberrant epigenetic activation. WASP interacts with dozens of nuclear speckle constituents and constrains SRSF2 mobility. Using an optogenetic system, we showed that WASP forms phase-separated condensates that encompasses SRSF2, nascent RNA and active Pol II. The role of WASP in gene body condensates is corroborated by ChIPseq and RIPseq. Together our data reveal that WASP is a nexus regulator of RNA splicing that controls the transcription of splicing factors epigenetically and the dynamics of the splicing machinery through liquid-liquid phase separation.
Topics: Alternative Splicing; Cell Nucleus; Humans; RNA Polymerase II; RNA Splicing Factors; RNA-Binding Proteins; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 35752626
DOI: 10.1038/s41467-022-31220-8 -
Frontiers in Immunology 2021Gene therapy is an innovative treatment for Primary Immune Deficiencies (PIDs) that uses autologous hematopoietic stem cell transplantation to deliver stem cells with... (Review)
Review
Gene therapy is an innovative treatment for Primary Immune Deficiencies (PIDs) that uses autologous hematopoietic stem cell transplantation to deliver stem cells with added or edited versions of the missing or malfunctioning gene that causes the PID. Initial studies of gene therapy for PIDs in the 1990-2000's used integrating murine gamma-retroviral vectors. While these studies showed clinical efficacy in many cases, especially with the administration of marrow cytoreductive conditioning before cell re-infusion, these vectors caused genotoxicity and development of leukoproliferative disorders in several patients. More recent studies used lentiviral vectors in which the enhancer elements of the long terminal repeats self-inactivate during reverse transcription ("SIN" vectors). These SIN vectors have excellent safety profiles and have not been reported to cause any clinically significant genotoxicity. Gene therapy has successfully treated several PIDs including Adenosine Deaminase Severe Combined Immunodeficiency (SCID), X-linked SCID, Artemis SCID, Wiskott-Aldrich Syndrome, X-linked Chronic Granulomatous Disease and Leukocyte Adhesion Deficiency-I. In all, gene therapy for PIDs has progressed over the recent decades to be equal or better than allogeneic HSCT in terms of efficacy and safety. Further improvements in methods should lead to more consistent and reliable efficacy from gene therapy for a growing list of PIDs.
Topics: Genetic Therapy; Granulomatous Disease, Chronic; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Primary Immunodeficiency Diseases; Severe Combined Immunodeficiency; Treatment Outcome; Wiskott-Aldrich Syndrome; X-Linked Combined Immunodeficiency Diseases
PubMed: 33717203
DOI: 10.3389/fimmu.2021.648951 -
Blood Mar 2022Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients affected by Wiskott-Aldrich syndrome (WAS). Reported HSCT...
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients affected by Wiskott-Aldrich syndrome (WAS). Reported HSCT outcomes have improved over time with respect to overall survival, but some studies have identified older age and HSCT from alternative donors as risk factors predicting poorer outcome. We analyzed 197 patients undergoing transplant at European Society for Blood and Marrow Transplantation centers between 2006 and 2017 who received conditioning as recommended by the Inborn Errors Working Party (IEWP): either busulfan (n = 103) or treosulfan (n = 94) combined with fludarabine ± thiotepa. After a median follow-up post-HSCT of 44.9 months, 176 patients were alive, resulting in a 3-year overall survival of 88.7% and chronic graft-versus-host disease (GVHD)-free survival (events include death, graft failure, and severe chronic GVHD) of 81.7%. Overall survival and chronic GVHD-free survival were not significantly affected by conditioning regimen (busulfan- vs treosulfan-based), donor type (matched sibling donor/matched family donor vs matched unrelated donor/mismatched unrelated donor vs mismatched family donor), or period of HSCT (2006-2013 vs 2014-2017). Patients aged <5 years at HSCT had a significantly better overall survival. The overall cumulative incidences of grade III to IV acute GVHD and extensive/moderate/severe chronic GVHD were 6.6% and 2.1%, respectively. Patients receiving treosulfan-based conditioning had a higher incidence of graft failure and mixed donor chimerism and more frequently underwent secondary procedures (second HSCT, unconditioned stem cell boost, donor lymphocyte infusion, or splenectomy). In summary, HSCT for WAS with conditioning regimens currently recommended by IEWP results in excellent survival and low rates of GVHD, regardless of donor or stem cell source, but age ≥5 years remains a risk factor for overall survival.
Topics: Busulfan; Child, Preschool; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Retrospective Studies; Tissue Donors; Transplantation Conditioning; Treatment Outcome; Wiskott-Aldrich Syndrome
PubMed: 35100336
DOI: 10.1182/blood.2021014687 -
The Journal of Experimental Medicine Jan 2020Ex vivo retrovirally mediated gene therapy has been shown within the last 20 yr to correct the T cell immunodeficiency caused by γc-deficiency (SCID X1) and adenosine... (Review)
Review
Ex vivo retrovirally mediated gene therapy has been shown within the last 20 yr to correct the T cell immunodeficiency caused by γc-deficiency (SCID X1) and adenosine deaminase (ADA) deficiency. The rationale was brought up by the observation of the revertant of SCIDX1 and ADA deficiency as a kind of natural gene therapy. Nevertheless, the first attempts of gene therapy for SCID X1 were associated with insertional mutagenesis causing leukemia, because the viral enhancer induced transactivation of oncogenes. Removal of this element and use of a promoter instead led to safer but still efficacious gene therapy. It was observed that a fully diversified T cell repertoire could be generated by a limited set (<1,000) of progenitor cells. Further advances in gene transfer technology, including the use of lentiviral vectors, has led to success in the treatment of Wiskott-Aldrich syndrome, while further applications are pending. Genome editing of the mutated gene may be envisaged as an alternative strategy to treat SCID diseases.
Topics: Adenosine Deaminase; Agammaglobulinemia; Animals; Gene Editing; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Interleukin Receptor Common gamma Subunit; Leukemia; Mutagenesis, Insertional; Mutation, Missense; Retroviridae; Severe Combined Immunodeficiency; T-Lymphocytes; Wiskott-Aldrich Syndrome; X-Linked Combined Immunodeficiency Diseases
PubMed: 31826240
DOI: 10.1084/jem.20190607 -
Scientific Reports Feb 2021Wiskott Aldrich syndrome (WAS) is a rare disease and hematopoietic stem cell transplant (HCT) is considered the treatment modality of choice for WAS. We conducted a...
Wiskott Aldrich syndrome (WAS) is a rare disease and hematopoietic stem cell transplant (HCT) is considered the treatment modality of choice for WAS. We conducted a cross-sectional analysis on the KIDS' pediatric inpatient database and compared hospitalization rates, complications and healthcare utilizations in the transplant and non-transplant arms. Of the 383 pediatric admissions with diagnosis of WAS between 2006-2012, 114 underwent transplant and 269 did not. The non-transplant arm included older children, female patients and more African Americans. Death rates, income and payer source were similar in both arms, however the total charge for each admission was higher in the transplant arm. Emergency room visits were similar but non-elective admissions were more in the non-transplant arm. Length of stay was prolonged in the transplant arm. When comparing morbidities, lymphomas, ulcerative colitis and autoimmune complications of WAS were seen only in the non-transplant arm. Our study shows that transplant is the largest contributor to healthcare utilization in WAS patients. We identified healthcare disparities based on race and socioeconomic status and found that this rare disease is being appropriately directed to centers with HCT expertise. We noted a change in practice moving away from splenectomy in WAS patients.
Topics: Child, Preschool; Female; Healthcare Disparities; Hematopoietic Stem Cell Transplantation; Hospital Mortality; Humans; Male; Population Groups; Social Class; Wiskott-Aldrich Syndrome
PubMed: 33633315
DOI: 10.1038/s41598-021-84328-0 -
Clinical and Experimental Dental... Feb 2022Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency, characterized by micro-thrombocytopenia, recurrent infections, and eczema. This study aims to... (Review)
Review
OBJECTIVE
Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency, characterized by micro-thrombocytopenia, recurrent infections, and eczema. This study aims to describe common oral manifestations and evaluate oral microbioma of WAS patients.
MATERIAL AND METHODS
In this cohort study, 11 male WAS patients and 16 male healthy controls were evaluated in our Center between 2010 and 2018. Data about clinical history, oral examination, Gingival Index (GI) and Plaque Index (PI) were collected from both groups. Periodontal microbiological flora was evaluated on samples of the gingival sulcus.
RESULTS
WAS subjects presented with premature loss of deciduous and permanent teeth, inclusions, eruption disturbance, and significantly worse GI and PI. They also showed a trend toward a higher total bacterial load. Fusobacterium nucleatum, reported to contribute to periodontitis onset, was the most prevalent bacteria, together with Porphyromonas gingivalis and Tannerella forsythia.
CONCLUSIONS
Our data suggest that WAS patients are at greater risk of alterations in the oral cavity. The statistically higher incidence of periodontitis and the trend to higher prevalence of potentially pathological bacterial species in our small cohort, that should be confirmed in future in a larger population, underline the importance of dentistry monitoring as part of the multidisciplinary management of WAS patients.
Topics: Aggregatibacter actinomycetemcomitans; Child; Cohort Studies; Female; Humans; Male; Microbiota; Periodontitis; Prevotella intermedia; Wiskott-Aldrich Syndrome
PubMed: 35199474
DOI: 10.1002/cre2.503 -
Scandinavian Journal of Immunology Jan 2022Wiskott-Aldrich syndrome (WAS) also called the eczema-thrombocytopenia-immunodeficiency syndrome is a primary immunodeficiency disease with X-linked recessive...
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).
Topics: China; DNA Mutational Analysis; Eczema; Family; Female; Humans; Infant; Leukocytes, Mononuclear; Male; Mean Platelet Volume; Mutation; Thrombocytopenia; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 34758123
DOI: 10.1111/sji.13115 -
FEBS Letters Dec 2011Wiskott-Aldrich Syndrome (WAS) is a X-linked primary immunodeficiency disorder also marked by a very high (up to 70%) incidence of autoimmunity. Wiskott-Aldrich Syndrome... (Review)
Review
Wiskott-Aldrich Syndrome (WAS) is a X-linked primary immunodeficiency disorder also marked by a very high (up to 70%) incidence of autoimmunity. Wiskott-Aldrich Syndrome arises from mutations in the Wiskott-Aldrich Syndrome protein (WASp), a cytoplasmic protein that links signaling by cell surface receptors such as the T-cell receptor and integrins to actin polymerization. WASp promotes the functions of multiple cell types that support immune responses, but also is important for the function of regulatory T cells and in TCR-induced apoptosis, two negative mechanisms of immune regulation that maintain peripheral immune tolerance. Here we review the nature of immune defects and autoimmunity in WAS and WASp deficient mice and discuss how this single gene defect can simultaneously impair immune responses to pathogens and promote autoimmunity. The myriad cellular immune defects found in WAS make this Mendelian syndrome an interesting model for the study of more complex immune diseases that arise from the interplay of environmental and multiple genetic risk factors.
Topics: Animals; Autoimmune Diseases; Autoimmunity; Humans; Models, Immunological; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 22036785
DOI: 10.1016/j.febslet.2011.10.031 -
Medicine Dec 2022Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency disorder. Despite our enormous progress in the strategies used to diagnose, treat, and cure...
BACKGROUND
Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency disorder. Despite our enormous progress in the strategies used to diagnose, treat, and cure WAS, no bibliometric studies have been performed in this research field. This study explored the trends in WAS research through a bibliometric analysis evaluating relevant literature quantitatively and qualitatively.
METHODS
The literature concerning WAS from 2001 to 2021 was retrieved from the Science Citation Index Expanded (SCI-expanded) of the Web of Science Core Collection database. Acquired data were then visually analyzed using CiteSpace and VOSviewer.
RESULTS
2036 papers were included in the final analysis. The annual publication outputs reached its peak in 2013 but declined in recent years. The dominant position of the United States in WAS research was quite obvious. Harvard University (USA), University College London (UK), and Inserm (France) were the three most prolific institutions. Adrian J. Thrasher exerted significant publication impact and made the most notable contributions in the field of WAS. Blood was the most influential journal with the highest publication outputs, and nearly all the top 10 journals and co-cited journals belonged to Q1. Immune dysregulation, thrombocytopenia, syndrome protein deficiency, stem cell, mutation, and diagnosis were the keywords with the strongest citation burst.
CONCLUSION
From 2001 to 2021, the United States was a global leader in the WAS research. Collaboration between countries and institutions is expected to deepen and strengthen in the future. Research hotspots included pathogenesis, clinical manifestations, diagnosis, and therapy. Our results suggest a greater understanding of the mechanistic underpinnings of immune dysfunction in WAS patients, the application of targeted therapies for individual complications, and the development of curative approaches, which will remain research hotspots in the future.
Topics: Humans; Wiskott-Aldrich Syndrome; Thrombocytopenia; Bibliometrics; Databases, Factual; France
PubMed: 36550896
DOI: 10.1097/MD.0000000000032347