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Frontiers in Immunology 2021Wiskott Aldrich syndrome (WAS) is characterized by bleeding manifestations, recurrent infections, eczema, autoimmunity, and malignancy. Over the last decade, improved...
BACKGROUND
Wiskott Aldrich syndrome (WAS) is characterized by bleeding manifestations, recurrent infections, eczema, autoimmunity, and malignancy. Over the last decade, improved awareness and better in-house diagnostic facilities at several centers in India has resulted in increased recognition of WAS. This study reports collated data across major primary immunodeficiency diseases (PID) centers in India that are involved in care of children with WAS and highlights the varied clinical presentations, genetic profile, and outcomes of patients in India.
METHODS
Request to share data was sent to multiple centers in India that are involved in care and management of patients with PID. Six centers provided requisite data that were compiled and analyzed.
RESULTS
In this multi-institutional cohort, clinical details of 108 patients who had a provisional diagnosis of WAS were received. Of these, 95 patients with 'definite WAS' were included Fourteen patients were classified as XLT and 81 patients as WAS. Median age at onset of symptoms of patients was 3 months (IQR 1.6, 6.0 months) and median age at diagnosis was 12 months (IQR 6,48 months). Clinical profile included bleeding episodes (92.6%), infections (84.2%), eczema (78.9%), various autoimmune manifestations (40%), and malignancy (2.1%). DNA analysis revealed 47 variants in 67 cases. Nonsense and missense variants were the most common (28.4% each), followed by small deletions (19.4%), and splice site defects (16.4%). We also report 24 novel variants, most of these being frameshift and nonsense mutations resulting in premature termination of protein synthesis. Prophylactic intravenous immunoglobulin (IVIg) was initiated in 52 patients (54.7%). Hematopoietic stem cell transplantation (HSCT) was carried out in 25 patients (26.3%). Of those transplanted, disease-free survival was seen in 15 patients (60%). Transplant related mortality was 36%. Outcome details were available for 89 patients. Of these, 37% had died till the time of this analysis. Median duration of follow-up was 36 months (range 2 weeks- 12 years; IQR 16.2 months- 70 months).
CONCLUSIONS
We report the first nationwide cohort of patients with WAS from India. Bleeding episodes and infections are common manifestations. Mortality continues to be high as curative therapy is not accessible to most of our patients.
Topics: Age Factors; Child, Preschool; Developing Countries; Disease-Free Survival; Female; Genetic Predisposition to Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulins, Intravenous; India; Infant; Male; Mutation; Phenotype; Risk Assessment; Risk Factors; Time Factors; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 33936041
DOI: 10.3389/fimmu.2021.627651 -
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 2014
Review
PubMed: 25386182
DOI: 10.3389/fimmu.2014.00539 -
Journal of Blood Medicine 2021The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder caused by mutations in the gene resulting in congenital thrombocytopenia, eczema, recurrent infections and an... (Review)
Review
The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder caused by mutations in the gene resulting in congenital thrombocytopenia, eczema, recurrent infections and an increased incidence of autoimmune diseases and malignancies. Without curative therapies, affected patients have diminished life expectancy and reduced quality of life. Since WAS protein (WASP) is constitutively expressed only in hematopoietic stem cell-derived lineages, hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) are well suited to correct the hematologic and immunologic defects. Advances in high-resolution HLA typing, new techniques to prevent GvHD allowing the use of haploidentical donors, and the introduction of reduced intensity conditioning regimens with myeloablative features have increased overall survival (OS) to over 90%. The development of GT for WAS has provided basic knowledge into vector selection and random integration of various viral vectors into the genome, with the possibility of inducing leukemogenesis. After trials and errors, inactivating lentiviral vectors carrying the WAS gene were successfully evaluated in clinical trials, demonstrating cure of the disease except for insufficient resolution of the platelet defect. Thus, 50 years of clinical evaluation, genetic exploration and extensive clinical trials, a lethal syndrome has turned into a curable disorder.
PubMed: 34149291
DOI: 10.2147/JBM.S232650 -
Nature Medicine Jan 2022Patients with Wiskott-Aldrich syndrome (WAS) lacking a human leukocyte antigen-matched donor may benefit from gene therapy through the provision of gene-corrected,...
Patients with Wiskott-Aldrich syndrome (WAS) lacking a human leukocyte antigen-matched donor may benefit from gene therapy through the provision of gene-corrected, autologous hematopoietic stem/progenitor cells. Here, we present comprehensive, long-term follow-up results (median follow-up, 7.6 years) (phase I/II trial no. NCT02333760 ) for eight patients with WAS having undergone phase I/II lentiviral vector-based gene therapy trials (nos. NCT01347346 and NCT01347242 ), with a focus on thrombocytopenia and autoimmunity. Primary outcomes of the long-term study were to establish clinical and biological safety, efficacy and tolerability by evaluating the incidence and type of serious adverse events and clinical status and biological parameters including lentiviral genomic integration sites in different cell subpopulations from 3 years to 15 years after gene therapy. Secondary outcomes included monitoring the need for additional treatment and T cell repertoire diversity. An interim analysis shows that the study meets the primary outcome criteria tested given that the gene-corrected cells engrafted stably, and no serious treatment-associated adverse events occurred. Overall, severe infections and eczema resolved. Autoimmune disorders and bleeding episodes were significantly less frequent, despite only partial correction of the platelet compartment. The results suggest that lentiviral gene therapy provides sustained clinical benefits for patients with WAS.
Topics: Adolescent; Adult; Child; Child, Preschool; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Genetic Therapy; Genetic Vectors; Hematopoietic Stem Cell Transplantation; Humans; Infant; Lentivirus; Treatment Outcome; Wiskott-Aldrich Syndrome; Young Adult
PubMed: 35075289
DOI: 10.1038/s41591-021-01641-x -
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 -
The Journal of Neuroscience : the... Aug 2020Oligodendrocyte myelination depends on actin cytoskeleton rearrangement. Neural Wiskott-Aldrich syndrome protein(N-Wasp) is an actin nucleation factor that promotes...
Oligodendrocyte myelination depends on actin cytoskeleton rearrangement. Neural Wiskott-Aldrich syndrome protein(N-Wasp) is an actin nucleation factor that promotes polymerization of branched actin filaments. N-Wasp activity is essential for myelin membrane wrapping by Schwann cells, but its role in oligodendrocytes and CNS myelination remains unknown. Here we report that oligodendrocytes-specific deletion of in mice of both sexes resulted in hypomyelination (i.e., reduced number of myelinated axons and thinner myelin profiles), as well as substantial focal hypermyelination reflected by the formation of remarkably long myelin outfolds. These myelin outfolds surrounded unmyelinated axons, neuronal cell bodies, and other myelin profiles. The latter configuration resulted in pseudo-multimyelin profiles that were often associated with axonal detachment and degeneration throughout the CNS, including in the optic nerve, corpus callosum, and the spinal cord. Furthermore, developmental analysis revealed that myelin abnormalities were already observed during the onset of myelination, suggesting that they are formed by aberrant and misguided elongation of the oligodendrocyte inner lip membrane. Our results demonstrate that N-Wasp is required for the formation of normal myelin in the CNS. They also reveal that N-Wasp plays a distinct role in oligodendrocytes compared with Schwann cells, highlighting a difference in the regulation of actin dynamics during CNS and PNS myelination. Myelin is critical for the normal function of the nervous system by facilitating fast conduction of action potentials. During the process of myelination in the CNS, oligodendrocytes undergo extensive morphological changes that involve cellular process extension and retraction, axonal ensheathment, and myelin membrane wrapping. Here we present evidence that N-Wasp, a protein regulating actin filament assembly through Arp2/3 complex-dependent actin nucleation, plays a critical role in CNS myelination, and its absence leads to several myelin abnormalities. Our data provide an important step into the understanding of the molecular mechanisms underlying CNS myelination.
Topics: Animals; Corpus Callosum; Female; Male; Mice; Mice, Inbred C57BL; Myelin Sheath; Oligodendroglia; Optic Nerve; Spinal Cord; Wiskott-Aldrich Syndrome Protein, Neuronal
PubMed: 32601246
DOI: 10.1523/JNEUROSCI.0912-20.2020 -
Nature Communications May 2023Mobilized peripheral blood is increasingly used instead of bone marrow as a source of autologous hematopoietic stem/progenitor cells for ex vivo gene therapy. Here, we... (Clinical Trial)
Clinical Trial
Mobilized peripheral blood is increasingly used instead of bone marrow as a source of autologous hematopoietic stem/progenitor cells for ex vivo gene therapy. Here, we present an unplanned exploratory analysis evaluating the hematopoietic reconstitution kinetics, engraftment and clonality in 13 pediatric Wiskott-Aldrich syndrome patients treated with autologous lentiviral-vector transduced hematopoietic stem/progenitor cells derived from mobilized peripheral blood (n = 7), bone marrow (n = 5) or the combination of the two sources (n = 1). 8 out of 13 gene therapy patients were enrolled in an open-label, non-randomized, phase 1/2 clinical study (NCT01515462) and the remaining 5 patients were treated under expanded access programs. Although mobilized peripheral blood- and bone marrow- hematopoietic stem/progenitor cells display similar capability of being gene-corrected, maintaining the engineered grafts up to 3 years after gene therapy, mobilized peripheral blood-gene therapy group shows faster neutrophil and platelet recovery, higher number of engrafted clones and increased gene correction in the myeloid lineage which correlate with higher amount of primitive and myeloid progenitors contained in hematopoietic stem/progenitor cells derived from mobilized peripheral blood. In vitro differentiation and transplantation studies in mice confirm that primitive hematopoietic stem/progenitor cells from both sources have comparable engraftment and multilineage differentiation potential. Altogether, our analyses reveal that the differential behavior after gene therapy of hematopoietic stem/progenitor cells derived from either bone marrow or mobilized peripheral blood is mainly due to the distinct cell composition rather than functional differences of the infused cell products, providing new frames of references for clinical interpretation of hematopoietic stem/progenitor cell transplantation outcome.
Topics: Humans; Child; Animals; Mice; Bone Marrow; Hematopoietic Stem Cells; Hematopoietic Stem Cell Transplantation; Genetic Therapy; Wiskott-Aldrich Syndrome; Granulocyte Colony-Stimulating Factor
PubMed: 37244942
DOI: 10.1038/s41467-023-38448-y -
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 -
Frontiers in Cell and Developmental... 2021Signal transduction regulates the proper function of T cells in an immune response. Upon binding to its specific ligand associated with major histocompatibility complex... (Review)
Review
Signal transduction regulates the proper function of T cells in an immune response. Upon binding to its specific ligand associated with major histocompatibility complex (MHC) molecules on an antigen presenting cell, the T cell receptor (TCR) initiates intracellular signaling that leads to extensive actin polymerization. Wiskott-Aldrich syndrome protein (WASp) is one of the actin nucleation factors that is recruited to TCR microclusters, where it is activated and regulates actin network formation. Here we highlight the research that has focused on WASp-deficient T cells from both human and mice in TCR-mediated signal transduction. We discuss the role of WASp in proximal TCR signaling as well as in the Ras/Rac-MAPK (mitogen-activated protein kinase), PKC (protein kinase C) and Ca-mediated signaling pathways.
PubMed: 34169073
DOI: 10.3389/fcell.2021.674572