-
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 -
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 -
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 -
Proceedings of the National Academy of... Aug 2023Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by various disabling symptoms including exercise intolerance and is diagnosed in the absence...
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by various disabling symptoms including exercise intolerance and is diagnosed in the absence of a specific cause, making its clinical management challenging. A better understanding of the molecular mechanism underlying this apparent bioenergetic deficiency state may reveal insights for developing targeted treatment strategies. We report that overexpression of (), here identified in a 38-y-old woman suffering from long-standing fatigue and exercise intolerance, can disrupt mitochondrial respiratory supercomplex formation and is associated with endoplasmic reticulum (ER) stress. Increased expression of in transgenic mice markedly decreased their treadmill running capacity with concomitantly impaired respiratory supercomplex assembly and reduced complex IV levels in skeletal muscle mitochondria. WASF3 induction by ER stress using endotoxin, well known to be associated with fatigue in humans, also decreased skeletal muscle complex IV levels in mice, while decreasing WASF3 levels by pharmacologic inhibition of ER stress improved mitochondrial function in the cells of the patient with chronic fatigue. Expanding on our findings, skeletal muscle biopsy samples obtained from a cohort of patients with ME/CFS showed increased WASF3 protein levels and aberrant ER stress activation. In addition to revealing a potential mechanism for the bioenergetic deficiency in ME/CFS, our study may also provide insights into other disorders associated with fatigue such as rheumatic diseases and long COVID.
Topics: Animals; Female; Humans; Mice; COVID-19; Fatigue Syndrome, Chronic; Mitochondria; Post-Acute COVID-19 Syndrome; Respiration; Wiskott-Aldrich Syndrome Protein Family; Mice, Transgenic
PubMed: 37579159
DOI: 10.1073/pnas.2302738120 -
Current Biology : CB May 2021Dynamic rearrangement of the actin cytoskeleton drives a myriad of processes in eukaryotic cells, such as cell migration and vesicle trafficking, and its dysregulation...
Dynamic rearrangement of the actin cytoskeleton drives a myriad of processes in eukaryotic cells, such as cell migration and vesicle trafficking, and its dysregulation is deeply associated with various diseases, including cancer, immune deficiency, and neurological disorders. Members of the Wiskott-Aldrich syndrome protein (WASP) family, including WASP, N-WASP, WAVE, WASH, WHAMM, JMY, and the recently identified WHIMP, are ubiquitous regulators of actin dynamics. Although each WASP-family protein uses a different regulatory mechanism and participates in distinct cellular processes, they all act by integrating various upstream signals and transmitting them to their carboxy-terminal WCA (WH2-central-acidic, where WH2 stands for WASP homology 2) domain. This domain stimulates the actin nucleation activity of the Arp2/3 complex to promote the formation of new filaments from existing ones, creating branched actin networks that are crucial for dynamic deformations of membranes.
Topics: Actin Cytoskeleton; Actin-Related Protein 2-3 Complex; Actins; Cytoskeleton; Wiskott-Aldrich Syndrome Protein; Wiskott-Aldrich Syndrome Protein Family
PubMed: 34033782
DOI: 10.1016/j.cub.2021.01.086 -
The Application of Clinical Genetics 2021Wiskott-Aldrich syndrome (WAS) is an uncommon X-linked combined-immunodeficiency disorder characterized by a triad of thrombocytopenia, eczema, and immunodeficiency.... (Review)
Review
Wiskott-Aldrich syndrome (WAS) is an uncommon X-linked combined-immunodeficiency disorder characterized by a triad of thrombocytopenia, eczema, and immunodeficiency. Patients with WAS are also predisposed to autoimmunity and malignancy. Autoimmune manifestations have been reported in 26%-72% of patients with WAS. Autoimmunity is an independent predictor of poor prognosis and predisposes to malignancy. Development of autoimmunity is also an early pointer of the need for hematopoietic stem-cell transplantation. In this manuscript, we have collated the published data and present a narrative review on autoimmune manifestations in WAS. A summary of currently proposed immunopathogenic mechanisms and genetic variants associated with development of autoimmunity in WAS is also included.
PubMed: 34447261
DOI: 10.2147/TACG.S213920 -
European Journal of Immunology Nov 2017The Wiskott-Aldrich syndrome protein (WASP) participates in innate and adaptive immunity through regulation of actin cytoskeleton-dependent cellular processes, including... (Review)
Review
The Wiskott-Aldrich syndrome protein (WASP) participates in innate and adaptive immunity through regulation of actin cytoskeleton-dependent cellular processes, including immune synapse formation, cell signaling, migration and cytokine release. There is also emerging evidence for a direct role in nuclear transcription programmes uncoupled from actin polymerization. A deeper understanding of some of the more complex features of Wiskott Aldrich syndrome (WAS) itself, such as the associated autoimmunity and inflammation, has come from identification of defects in the number and function of anti-inflammatory myeloid cells and regulatory T and B cells, as well as defects in positive and negative B-cell selection. In this review we outline the cellular defects that have been characterized in both human WAS patients and murine models of the disease. We will emphasize in particular recent discoveries that provide a mechanistic insight into disease pathology, including lymphoid and myeloid cell homeostasis, immune synapse assembly and immune cell signaling.
Topics: Animals; Humans; Mice; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 28805251
DOI: 10.1002/eji.201646715 -
International Journal of Molecular... Jan 2021Increasing evidence indicates that cancer metastasis is regulated by specific genetic pathways independent of those controlling tumorigenesis and cancer growth. WASF3, a... (Review)
Review
Increasing evidence indicates that cancer metastasis is regulated by specific genetic pathways independent of those controlling tumorigenesis and cancer growth. WASF3, a Wiskott-Aldrich syndrome protein family member, appears to play a major role not only in the regulation of actin cytoskeleton dynamics but also in cancer cell invasion/metastasis. Recent studies have highlighted that WASF3 is a master regulator and acts as a pivotal scaffolding protein, bringing the various components of metastatic signaling complexes together both spatially and temporally. Herein, targeting WASF3 at the levels of transcription, protein stability, and phosphorylation holds great promise for metastasis suppression, regardless of the diverse genetic backgrounds associated with tumor development. This review focuses on the critical and distinct contributions of WASF3 in the regulation of signal pathways promoting cancer cell invasion and metastasis.
Topics: ATPases Associated with Diverse Cellular Activities; Animals; Cell Movement; Endoplasmic Reticulum Chaperone BiP; Gene Expression Regulation, Neoplastic; HSP70 Heat-Shock Proteins; Heat-Shock Proteins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Janus Kinase 2; Membrane Proteins; Mice; MicroRNAs; Mitochondrial Proteins; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphorylation; STAT3 Transcription Factor; Signal Transduction; Wiskott-Aldrich Syndrome Protein Family
PubMed: 33467681
DOI: 10.3390/ijms22020836