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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. Long-term monitoring of patients with Wiskott–Aldrich syndrome following lentiviral gene therapy shows a safe profile and a reduction in the frequency of autoimmune manifestations and bleeding events, despite incomplete platelet reconstitution.

Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency with severe platelet abnormalities and complex immunodeficiency. Although clinical gene therapy approaches using lentiviral vectors have produced encouraging results, full immune and platelet reconstitution is not always achieved. Here we show that a CRISPR/Cas9-based genome editing strategy allows the precise correction of WAS mutations in up to 60% of human hematopoietic stem and progenitor cells (HSPCs), without impairing cell viability and differentiation potential. Delivery of the editing reagents to WAS HSPCs led to full rescue of WASp expression and correction of functional defects in myeloid and lymphoid cells. Primary and secondary transplantation of corrected WAS HSPCs into immunodeficient mice showed persistence of edited cells for up to 26 weeks and efficient targeting of long-term repopulating stem cells. Finally, no major genotoxicity was associated with the gene editing process, paving the way for an alternative, yet highly efficient and safe therapy. In recent years, hematopoietic stem cells gene editing has emerged as a promising tool to treat blood disorders. Here the authors develop a CRISPR/Cas9-based genome editing strategy that allows the precise correction of Wiskott-Aldrich Syndrome in vitro and in vivo with high efficiency.

Wiskott–Aldrich syndrome (WAS) is caused by mutations in the WAS gene and is characterized by immunodeficiency, eczema and microthrombocytopenia. The molecular link between WAS mutations and microthrombocytopenia is unknown. Profilin1 (Pfn1) is a key actin-regulating protein that, besides actin, interacts with phosphoinositides and multiple proline-rich proteins, including the WAS protein (WASp)/WASp-interacting protein (WIP) complex. Here we report that mice with a megakaryocyte/platelet-specific Pfn1 deficiency display microthrombocytopenia due to accelerated turnover of platelets and premature platelet release into the bone marrow. Both Pfn1-null mouse platelets and platelets isolated from WAS patients contained abnormally organized and hyperstable microtubules. These results reveal an unexpected function of Pfn1 as a regulator of microtubule organization and point to a previously unrecognized mechanism underlying the platelet formation defect in WAS patients. Patients with mutations in the gene encoding the cytoskeleton regulator WAS have platelet defects. Here the authors show that the WAS-binding protein, Profilin1, is essential for platelet formation in mice, and that its deficiency reproduces the bleeding disorder of patients with WAS mutations.

Purpose Wiskott-Aldrich syndrome (WAS) is an X-linked genetic disorder characterized by distinctive features including microthrombocytopenia, eczema and recurrent infections. In the present study we report clinical, immunological and molecular spectrum of 41 WAS patients diagnosed over last five years. Methods Clinical and family history was collected from case records. Comprehensive immunological assessments including lymphocyte subset analysis, and flow cytometry based evaluation of WAS protein (WASP) expressions were performed in patients along with evaluation of carrier status in mothers. Genetic analysis was carried out with either Sanger sequencing or targeted exome sequencing. Results The patients included in this study presented at a median age of 9.5 months, with two adult cases. Clinical manifestations encompassed thrombocytopenia, eczema, bleeding, diarrhea, respiratory tract infections, CMV infection, and malignancy. Immunological phenotype revealed T cell lymphopenia, B cell lymphopenia, and elevated IgE levels. Flow cytometry analysis of WASP was performed in 36 cases out of which 68.42% demonstrated complete absent expression while others showed reduced expression. Genetic analysis highlighted that the majority of mutations affect the WH1 domain of WASP while both adult patients showed intronic mutations. Molecular Dynamics analysis conducted for the novel variants P398R and G33R showed an average RMSD (Å) higher than that of the wild type, indicating greater structural perturbations in WASP. Conclusion In the present study we have documented 56.09% novel WAS mutations in Indian cohort. Notably, the application of flow cytometry has emerged as a valuable and efficient diagnostic tool for identifying these WAS patients.

Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency associated with an increased susceptibility to herpesvirus infection and hematologic malignancy as well as a deficiency of NK cell function. It is caused by defective WAS protein (WASp). WASp facilitates filamentous actin (F-actin) branching and is required for F-actin accumulation at the NK cell immunological synapse and NK cell cytotoxicity ex vivo. Importantly, the function of WASp-deficient NK cells can be restored in vitro after exposure to IL-2, but the mechanisms underlying this remain unknown. Using a WASp inhibitor as well as cells from patients with WAS, we have defined a direct effect of IL-2 signaling upon F-actin that is independent of WASp function. We found that IL-2 treatment of a patient with WAS enhanced the cytotoxicity of their NK cells and the F-actin content at the immunological synapses formed by their NK cells. IL-2 stimulation of NK cells in vitro activated the WASp homolog WAVE2, which was required for inducing WASp-independent NK cell function, but not for baseline activity. Thus, WAVE2 and WASp define parallel pathways to F-actin reorganization and function in human NK cells; although WAVE2 was not required for NK cell innate function, it was accessible through adaptive immunity via IL-2. These results demonstrate how overlapping cytoskeletal activities can utilize immunologically distinct pathways to achieve synonymous immune function.

Purpose Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by eczema, microthrombocytopenia, and recurrent infections. This study evaluates the frequency of clinical manifestations and overall outcomes in WAS patients, comparing those who received hematopoietic stem cell transplantation (HSCT) with those who did not. Methods Thirty-eight boys with a definite diagnosis of WAS were retrospectively evaluated in the Immunology, Asthma, and Allergy Research Institute registry in Tehran from 2006 to 2023. Results The median ages at symptom onset, diagnosis, and delay to diagnosis were 3.5, 7.5, and 4.5 months, respectively. The clinical presentations include allergies in 38 (100%), infection in 37 (97.4%), hemorrhage in 36 (94.7%), autoimmunity in 14 (36.8%), and malignancies or myelodysplasia syndrome in 3 (7.9%) patients. Although microthrombocytopenia is a hallmark of WAS, 34.4% of our cases had normal platelet size. The WAS gene analysis in 36 of 38 patients identified six novel mutations. Sixteen patients underwent HSCT. Disease-free survival was reported in 10 (62.5%) of them, whereas 6 (37.5%) of them were deceased. The mortality rate in non-transplant patients was 15/22 (68.2%). Conclusion Most WAS patients experienced atopy, recurrent infections, and bleeding. Moreover, autoimmunity and malignancies have increased relative to the general population. Moreover, the mortality rate is high, especially among those who did not receive HSCT. Keeping in mind that thrombocytopenia alongside eczema and/or infection in a male infant can be the presentation of this fatal disease. Early diagnosis and treatment could be lifesaving and prevent severe morbidities.

Wiskott–Aldrich Syndrome (WAS), a rare X-linked disorder, features microthrombocytopenia, eczema, immunodeficiency, and elevated malignancy risk due to genomic instability. While prior studies noted DNA repair deficits, the kinetics of ionizing radiation-induced DSB repair in WAS patients remain unclear. This study aimed to characterize DSB repair dynamics and radiation sensitivity in WAS lymphocytes using γH2AX and 53BP1 markers. Lymphocytes from four WAS patients, their carrier mothers, and healthy controls were analyzed. Baseline DSBs were quantified in non-irradiated cells, and repair kinetics assessed post 2 Gy gamma irradiation over 24 h. Immunofluorescence staining for γH2AX (early DSB marker) and 53BP1 (repair facilitator) was performed at multiple time points, with foci quantified via confocal microscopy. Repair half-lives were calculated using exponential decay models. WAS patients exhibited 16–24 fold higher baseline γH2AX and 53BP1 foci than control (mean), indicating spontaneous genomic instability. Post-irradiation, DSB repair in WAS lymphocytes was significantly delayed, with the mean foci repair half-life (T½) in WAS patients being approximately 1.6-fold longer than that of the control (mean). At 24 h post-irradiation, WAS patients retained nearly twice the number of residual foci compared to healthy controls, while carrier mothers mirrored control repair efficiency. This study provides the first evidence of prolonged DSB repair kinetics in WAS patients, emphasising heightened radiosensitivity and genomic instability. These findings suggest tailored radiation strategies in WAS management, particularly for bone marrow transplantation or genotoxic therapies, to mitigate risks and optimize outcomes.

Key Points Wiskott–Aldrich Syndrome protein (WASP) is an important regulator of the actin cytoskeleton in haematopoietic cells. WASP-deficiency gives rise to the human disease Wiskott–Aldrich Syndrome (WAS), an X-linked primary immunodeficiency. Constitutively active mutations of WASP have recently been described to give rise to a distinct human disease: X-linked neutropenia. WASP activity is attenuated by multiple signalling pathways downstream of surface receptors. Conformational change, phosphorylation and degradation are important mechanisms. Although WASP does not seem to have a key role in haematopoiesis, WASP confers selective advantage for many mature haematopoietic cell types and is emerging as a key regulator of lymphocyte homeostasis. WASP is required for a diverse range of cell functions in innate and adaptive immune cells. These relate both to the role of WASP in cytoskelatal rearrangement and as an intrinsic signalling molecule. Autoimmunity is an important feature of WAS which is poorly understood. Recent studies suggest that defective regulatory T cell function is an important component. Insights into the basic mechanisms of WASP-associated disease are advancing our understanding of immune regulation with wider application, and this allows the potential for future therapeutic benefit. As a key regulator of the actin cytoskeleton, Wiskott–Aldrich syndrome protein (WASP) is involved in diverse immune responses, including leukocyte migration and activation. This Review describes how various mutations in mice and humans have led us to a greater appreciation of the many immunological functions of WASP. The Wiskott–Aldrich syndrome protein (WASP) is an important regulator of the actin cytoskeleton that is required for many haematopoietic and immune cell functions, including effective migration, phagocytosis and immune synapse formation. Loss of WASP activity leads to Wiskott–Aldrich syndrome, an X-linked disease that is associated with defects in a broad range of cellular processes, resulting in complex immunodeficiency, autoimmunity and microthrombocytopenia. Intriguingly, gain of function mutations cause a separate disease that is mainly characterized by neutropenia. Here, we describe recent insights into the cellular mechanisms of these two related, but distinct, human diseases and discuss their wider implications for haematopoiesis, immune function and autoimmunity.

Mycolactone is a diffusible lipid secreted by the human pathogen Mycobacterium ulcerans, which induces the formation of open skin lesions referred to as Buruli ulcers. Here, we show that mycolactone operates by hijacking the Wiskott-Aldrich syndrome protein (WASP) family of actin-nucleating factors. By disrupting WASP autoinhibition, mycolactone leads to uncontrolled activation of ARP2/3-mediated assembly of actin in the cytoplasm. In epithelial cells, mycolactone-induced stimulation of ARP2/3 concentrated in the perinuclear region, resulting in defective cell adhesion and directional migration. In vivo injection of mycolactone into mouse ears consistently altered the junctional organization and stratification of keratinocytes, leading to epidermal thinning, followed by rupture. This degradation process was efficiently suppressed by coadministration of the N-WASP inhibitor wiskostatin. These results elucidate the molecular basis of mycolactone activity and provide a mechanism for Buruli ulcer pathogenesis. Our findings should allow for the rationale design of competitive inhibitors of mycolactone binding to N-WASP, with anti-Buruli ulcer therapeutic potential.

The authors report the long-term (up to 3 years) correction of the Wiskott–Aldrich syndrome in two patients through retroviral infection of CD34+ hematopoietic cells after busulfan-induced transient myelosuppression. The Wiskott–Aldrich syndrome (WAS) is a complex primary immunodeficiency disorder that is characterized by recurrent infections, thrombocytopenia, eczema, and autoimmunity 1 , 2 and caused by mutations in WAS . 3 Its gene product, WAS protein (WASP), is a key regulator of actin polymerization in hematopoietic cells, with domains involved in signaling, cell locomotion, and immunologic-synapse formation. 4 The complex biologic features of this disease result from multiple dysfunctions in different subgroups of leukocytes, including defective function of T and B cells, disturbed formation of the NK-cell immunologic synapse, and impaired migratory responses in all leukocyte subgroups. 4 , 5 Severe WAS leads to an early . . .