RARE DISEASE
Wiskott-Aldrich syndrome
Wiskott-Aldrich syndrome
Wiskott-Aldrich syndrome
Synonyms: Eczema-thrombocytopenia-immunodeficiency syndrome, WAS
Synonyms: Eczema-thrombocytopenia-immunodeficiency syndrome, WAS
Synonyms: Eczema-thrombocytopenia-immunodeficiency syndrome, WAS
Drug discovery
8
drugs
With orphan designations
Overview
Wiskott-Aldrich syndrome (WAS) is an X-linked recessive primary immunodeficiency caused by mutations in the WAS gene, leading to defective Wiskott-Aldrich syndrome protein (WASP). Clinical features include thrombocytopenia (small platelets), eczema, recurrent infections, autoimmune complications, and increased lymphoma/leukemia risk. Definitive treatment is hematopoietic stem cell transplantation (HSCT), while gene therapy and supportive care (antibiotics, immunoglobulin replacement, platelet transfusions) manage symptoms [1][3][6][10][15][20].
Burden
Untreated patients face mortality from infections (30%), bleeding (20%), or malignancies (15–20%), with a median life expectancy of 15–20 years [3][10][15][18].
Autoimmune diseases (hemolytic anemia, vasculitis) occur in 26–72% of cases, complicating management [10][13][15].
HSCT carries risks of graft failure (5–10%) and GVHD; lifelong monitoring for malignancy is required post-treatment [12][15][18].
Therapies
HSCT: Curative, with >80% survival using matched donors; optimal outcomes if performed before age 2 [2][3][15].
Gene therapy: Autologous stem cell gene correction using lentiviral vectors shows long-term efficacy in resolving infections, eczema, and bleeding [7][8][15].
Supportive care: Prophylactic antibiotics, IVIG, platelet transfusions, and immunosuppressants for autoimmune complications [1][3][12][16].
Categories: rare genetic diseases, rare hematological diseases, rare immunological diseases, rare neoplastic diseases, rare skin diseases, rare transplant-related disorders
Research Papers
614 drug discovery papers about Wiskott-Aldrich syndrome, with 4 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
614 drug discovery papers about Wiskott-Aldrich syndrome, with 4 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-17 | Parthenolide boosts megakaryocyte maturation and restores platelet responses in Wiskott–Aldrich syndrome
Abstract Wiskott-Aldrich syndrome (WAS) is an inborn error of immunity with a broad disease spectrum, classified into class I (late onset) or II (early onset) variants. Thrombocytopenia and small platelets are the most consistent findings among patients, difficult to treat and related to development of autoimmunity. To identify new treatment options for thrombocytopenia in WAS, we developed a FACS-based screening for drug repurposing. We identified parthenolide as a lead small molecule that increased WASp abundance in cells with residual WASp expression. Using the megakaryocytic MEG-01 cells, gene edited to express WAS class I and II genetic variants, parthenolide induced megakaryocyte maturation as evident by upregulation of CD61, increased cell size and complexity, increased phosphorylation of ERK1/2, and higher DNA ploidy. We generated a new mouse model harboring a WAS class I missense variant WASp-R88C, corresponding to human WASp-R86C, with reduced expression of WASp. WASp-R88C mice had lower numbers of platelets compared to WT mice. Bone marrow-derived WASp-R88C and WASp-KO megakaryocytes, differentiated in the presence of parthenolide derivative, DMAPT, showed increased ploidy and upregulation of the maturation markers CD61, CD41 and CD42d, resulting in improved platelet production in vitro . Treatment with parthenolide derivative, DMAPT, led to increased platelet numbers in vivo in WASp-R88C mice and dampened the hyperactivation of WAS patient platelets by reducing thrombin-induced CD62P exposure after activation. The identification of parthenolide offers a promising therapeutic approach for WAS patients who are unresponsive or unsuitable for definitive therapies. Key points A FACS-based drug screen using degradation-prone class I WAS variants identifies parthenolide/DMAPT as a candidate that enhances megakaryocyte maturation and platelet production in vitro . Parthenolide/DMAPT thrombopoietic activity increases platelet production in vivo and restores improves cytoskeletal remodeling of WAS megakaryocytes and platelets.
2026-06-22 | An asymptomatic WASF1 truncation reveals pathogenic mechanism and therapeutic strategy for neurodevelopmental disorders.
Wiskott-Aldrich syndrome protein family member 1 (WASF1) truncating variants, such as c.1516C>T (p.Arg506Ter), are established causes of neurodevelopmental disorders (NDDs), but their underlying pathogenic mechanism remains debated. This study aimed to clarify the disease mechanism and identify potential therapeutic leads. We characterized a novel, asymptomatic WASF1 truncating variant (c.873delA) and compared its clinical and molecular consequences with those of the known pathogenic c.1516C>T variant. To target the likely pathogenic mutant protein, we performed high‑throughput virtual screening of the ZINC20 database. Despite a similar reduction in wild‑type protein levels, the c.873delA variant did not cause neurological symptoms, in contrast to c.1516C>T. This observation supports a dominant‑negative, gain‑of‑function, or altered protein function mechanism rather than simple haploinsufficiency; however, the precise mechanism could not be definitively resolved from the available genetic and protein expression data. Virtual screening identified ZINC000101023849 as a high‑affinity lead compound with favorable drug‑like properties. This study provides key evidence that WASF1‑related NDDs likely arise from a non‑haploinsufficiency mechanism and delivers a promising chemical lead for targeted therapy development. Further studies are needed to confirm the exact pathogenic mechanism and to validate the therapeutic potential of the identified compound.
2026-06-04 | The Forefront of Hematopoietic Stem Cell Transplantation: Focus on Inborn Errors of Immunity
Approximately 100 allogeneic hematopoietic stem cell transplantation (HSCT) procedures are performed for nonmalignant diseases in Japan annually. Inborn errors of immunity (IEIs) account for approximately one-third of patients with nonmalignant diseases (NMDs), which mainly comprises chronic granulomatous disease, severe combined immunodeficiency, Wiskott-Aldrich syndrome, and hyper IgM syndrome. Unlike hematological malignancies, no tumor cells do exist to be elucidated in the setting of allogeneic hematopoietic cell transplantation (HCT) for IEIs; therefore, intensive conditioning regimens, or rapid reduction or discontinuation of immunosuppressive agents to enhance alloreactive anti-tumor effect, is not required. However, because these patients do not generally receive pre-HCT chemotherapy, they can occasionally show sufficient immune response to reject donor cells, leading to higher risks of graft failure or mixed chimerism. Furthermore, patients with preexisting infection and organ failure due to the underlying disease itself or long-term use of immunosuppressive agents have a higher risk of severe early transplant-related adverse effects. These fundamental differences might affect the development of original transplant strategy for IEIs. Recent rapid advancements in transplant strategy have a great impact on allogeneic HSCT. Particularly, introduction of novel graft versus host disease (GVHD) prophylaxis, such as post-transplant cyclophosphamide and anti-CD52 antibody alemtuzumab, has enabled safe allogeneic HSCTs from alternative donors. Due to relatively higher post-transplant survival rates, it is essential to transplantation methods that ensure high survival rates while reducing the risk of early and late post-transplant complications. Therefore, there is a need for a scoring system for defining conditioning intensity and comprehensive assessments of late complications. In this session, I will provide an overview of the current status and future challenges of allogeneic HSCT for IEI, mainly based on the results of retrospective studies using a nationwide database established by the Japanese Data Center for Hematopoietic Cell Transplantation.
2026-04-08 | Pharmacological activation of WASp potentiates macrophage phagocytosis and enhances ibrutinib efficacy against mouse models of brain tumors.
Both primary and metastatic brain malignancies are fatal and highly infiltrated with tumor-associated macrophages (TAMs). Enhancing the phagocytosis of neoplastic cells by TAMs is pivotal for slowing tumor growth. Great endeavors have been made to develop tyrosine kinase inhibitors (TKIs) for brain malignancies, yet whether tumor-targeting TKIs affect the phagocytic capacity of TAMs remains largely unknown. In this preclinical study, we report that repurposing ibrutinib, a blood-brain barrier-penetrable TKI, effectively suppresses the growth of several primary and metastatic brain tumors highly expressing Bruton's tyrosine kinase (BTK) or bone marrow X-linked nonreceptor tyrosine kinase (BMX) but concurrently dampens the TAM phagocytic function. Mechanistically, BTK, which is activated in TAMs, interacts with and phosphorylates Wiskott-Aldrich syndrome protein (WASp) to organize the actin cytoskeleton, which is imperative for phagocytosis. Ibrutinib treatment disrupts BTK-mediated WASp activation, thereby compromising TAM phagocytic efficacy. Pharmacological activation of WASp by its selective small-molecular activator EG-011 restores the ibrutinib-impaired TAM engulfment of tumor cells and effectively improves ibrutinib efficacy in mice bearing glioblastomas, primary central nervous system lymphomas, and lung carcinoma brain metastases. Furthermore, elevated expression of phosphorylated BTK or phosphorylated WASp in TAMs correlates with an increased phagocytic TAM subset identified by single-cell RNA sequencing and correlates with prolonged patient survival in a cohort with glioblastoma. Our preclinical study highlights the necessity of evaluating the on-target, off-tumor attack of TAMs during TKI administration and provides a proof of concept for reinvigorating the TAM phagocytic function to achieve additional clinical benefit.
2026-04-03 | Abstract 4512: WASP activation by BM011 triggers mitochondrial collapse and aldolase-dependent glycolytic vulnerability in lymphoma.
Abstract Background. BM011 is the first-in-class WASP (Wiskott-Aldrich Syndrome Protein) activator (Spriano et al, 2024). WASP regulates cytoskeletal remodeling, immune synapse formation, vesicle trafficking, and mechano-metabolic coupling. Aberrant actin dynamics and rewiring of the WASP pathway contribute to proliferation, metabolic flexibility, and stress resistance in lymphomas and other cancers. Here, we investigated the mechanism of action of BM011 by combining transcriptomics, proteomics, and a genome-wide CRISPR-Cas9 knockout screen in lymphoma cells treated with the compound. Methods. JEKO1 mantle cell lymphoma cells were treated with BM011 for 8h and analyzed by RNA-Seq and mass spectrometry (MS). A genome-wide CRISPR-Cas9 knockout screen was conducted following 14-day exposure to BM011. Results. Proteomics revealed a strong downregulation of mitochondrial import and respiratory chain proteins in BM011-treated cells, while many RNAs coding for the same molecules were upregulated, consistent with an attempt to compensate for mitochondrial stress. Similarly, ribosomal proteins decreased, while ribosomal transcripts increased, suggesting a proteotoxic stress response and a translational offset. Stress-response genes (e.g., HSPA family), cytoskeleton, and apoptotic pathways were strongly induced, indicating proteotoxic pressure, cytoskeleton remodeling, and apoptosis induction following cytoskeletal forcing. At the genetic screen, the loss of many mitochondrial respiratory chain genes sensitized cells to BM011, confirming their importance in mitigating BM011-induced mitochondrial collapse. In contrast, the knockout of FUNDC2 and TIMM23, not part of the mitochondrial respiratory chain, conferred resistance, likely due to the interruption of mitochondrial quality control and decreased apoptosis upon BM011 treatment. The genetic screen also revealed a divergent vulnerability to glycolysis. Knockout of genes coding for enzymes of the upper glycolytic process (HK2, PFKM, PFKL, GPI, PFKFB3) conferred resistance, while knockout of genes coding for proteins in the lower part of glycolysis (PGK1, ENO1, PKM, PFKFB4) increased sensitivity. This pointed to aldolase and the fructose-1,6-bisphosphate node as a critical metabolic point. Aldolase can indeed bind to F-actin and WASP, inhibiting actin polymerization. Additionally, an excess of fructose-1,6-bisphosphate (F16bP) inhibits aldolase binding to F-actin. We proved that F16bP supplementation or aldolase inhibition increased the sensitivity of BM011 in otherwise resistant lymphoma cells. Conclusion. BM011-driven activation of WASP induces cytoskeletal stress, mitochondrial import failure, and a proteotoxic response, with upper-glycolysis and aldolase acting as a metabolic safety valve. These reveal druggable metabolic-cytoskeletal vulnerabilities in lymphoma. Citation Format: Filippo Spriano, Luciano Cascione, Stephen Croke, Digvijay Gahtory, Maurits van den Nieuwboer, Francesco Bertoni. WASP activation by BM011 triggers mitochondrial collapse and aldolase-dependent glycolytic vulnerability in lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4512.
proteins
2025-08-21 | Mechanistic understanding of Wiskott-Aldrich syndrome protein (WASp)-mediated epigenetic regulation of T helper cell differentiation in acute leukemia.
Wiskott-Aldrich syndrome protein (WASp) is exclusively expressed in hematopoietic cells, yet its role in leukemia remains poorly defined. This study investigates the epigenetic regulation of key immune genes by T helper (TH) cell transcription factors. Human CD4⁺ T cells from healthy donors and patients with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) were transfected with control CRISPR (CO), WASp knockout (WKO), and WASp overexpression (WOE) plasmids. Flow cytometry confirmed intracellular WASp staining in CO, WKO, and WOE CD4⁺ T cells. WOE leads to elevated mRNA levels of TH1-associated transcription factors, such as TBX21 and IFNγ. Notably, TBX21 enrichment increased significantly in WOE cells, while no such enrichment was observed for GATA3, RORC, or FOXP3. In addition, aberrant accumulation of R-loops at key gene loci, including TBX21, STAT1, ATM, and H2AFX, was prominently observed in WKO cells but not in WOE conditions. DNA methylation increased WKO cells but m6A levels were elevated under WOE conditions. Immunofluorescence analysis revealed much higher WASp expression in WOE but increased γH2A.X fluorescence in WKO. We found WASp stably interacts with the STAT1 binding region in the TBX21 promoter by molecular docking studies. Nitric oxide, reactive oxygen species, and glutathione levels were higher in WKO cells, while lactate dehydrogenase levels were increased in WOE samples. These findings collectively imply that WOE in acute leukemia promotes TH1 cell activity in a significant manner through epigenetic regulation and could be a potential therapeutic target. The online version contains supplementary material available at 10.1007/s13205-025-04474-4.
2025-03-06 | Molecular mechanism of Arp2/3 complex activation by nucleation-promoting factors and an actin monomer.
Arp (actin-related protein) 2/3 complex nucleates actin filament branches on the sides of preexisting actin filaments during cell and organelle movements. We used computer simulations of mammalian Arp2/3 complex to address fundamental questions about the mechanism. Metadynamics and umbrella free energy sampling simulations of the pathway revealed that a clash between the D-loop of Arp2 and Arp3 produces an energy barrier of 20 ± 6 kcal/mol between the inactive splayed and active short-pitch conformations of Arp2/3 complex. Atomistic molecular dynamics simulations showed that binding the CA motif of the nucleation-promoting factor Neuronal Wiskott-Aldrich Syndrome Protein (N-WASp) to inactive, splayed Arp2/3 complex shifts it toward the short-pitch active conformation and opens a binding site for an actin monomer on Arp3. Other simulations showed that this actin monomer stabilizes a transition state of Arp2/3 complex. These observations together with prior experimental work provide insights required to propose a physically grounded pathway for actin filament branch formation.
2024-11-17 | Wiskott-Aldrich syndrome protein maintains regulatory T cell tolerance by modulating their surface IL-2 receptor levels.
Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency condition caused by ablation of functional WAS protein (WASP) expression, and associated with susceptibility to infections, eczema, and autoimmunity. Regulatory T cell (Treg) defects are an important cause of autoimmunity in WAS. Currently, the mechanisms underlying cytoskeleton involvement in Treg-regulated autoimmunity remain unclear, and WAS is an excellent model for investigation of this question. Here, we examined patients with WAS and WASP knockout (WASp-/-) mice to uncover a new mechanism involving the actin nucleation promoting factor, WASP, in regulating Treg tolerance by modulating their surface IL-2 receptor (IL-2R) levels. Surface expression levels of IL-2R and its downstream signaling molecules, phosphoinositide 3-kinase/pSTAT5, are decreased in WASp-/- Tregs. Low dosage IL-2 combined with anti-IL-2 monoclonal antibody (IL2 complex) treatment can compensate for Treg deficiency in WAS in vitro and in vivo. Moreover, IL2 complex treatment relieved autoimmune colitis in WASp-/- mice. Reduced surface IL-2R is primarily caused by elevated IL-2R internalization and degradation, and lysosomal and endosomal genes associated with these processes are upregulated in WASp-/- Tregs. Finally, spatiotemporal analysis of dynamin and Neural Wiskott Aldrich Syndrome Protein (N-WASP) recruitment, by generating lipid bilayers and total internal reflection fluorescence microscopy, showed that WASP deficiency promoted IL-2R internalization and degradation by enhancing N-WASP activation. Consistently, N-WASP inhibition in Tregs using wiskostatin reduced IL-2R internalization. Together, our results reveal a novel intrinsic role of WASP in regulation of surface IL-2R dynamics in Tregs, highlighting a potential new therapeutic approach for autoimmune diseases.
2024-05-17 | Wiskott Aldrich syndrome protein (WASp)-deficient Th1 cells promote R-loop-driven transcriptional insufficiency and transcription-coupled nucleotide excision repair factor (TC-NER)-driven genome-instability in the pathogenesis of T cell acute lymphoblastic leukemia.
T-ALL is an aggressive hematological tumor that develops as the result of a multi-step oncogenic process which causes expansion of hematopoietic progenitors that are primed for T cell development to undergo malignant transformation and growth. Even though first-line therapy has a significant response rate, 40% of adult patients and 20% of pediatric patients will relapse. Therefore, there is an unmet need for treatment for relapsed/refractory T-ALL to develop potential targeted therapies. Pediatric T-ALL patient derived T cells were grown under either nonskewingTh0 or Th1-skewing conditions to further process for ChIP-qPCR, RDIP-qPCR and other RT-PCR assays. Endogenous WASp was knocked out using CRISPR-Cas9 and was confirmed using flow cytometry and western blotting. LC-MS/MS was performed to find out proteomic dataset of WASp-interactors generated from Th1-skewed, human primary Th-cells. DNA-damage was assessed by immunofluorescence confocal-imaging and single-cell gel electrophoresis (comet assay). Overexpression of RNaseH1 was also done to restore normal Th1-transcription in WASp-deficient Th1-skewed cells. We discovered that nuclear-WASp is required for suppressing R-loop production (RNA/DNA-hybrids) at Th1-network genes by ribonucleaseH2 (RNH2) and topoisomerase1. Nuclear-WASp is associated with the factors involved in preventing and dissolving R-loops in Th1 cells. In nuclear- WASp-reduced malignant Th1-cells, R-loops accumulate in vivo and are processed into DNA-breaks by transcription-coupled-nucleotide-excision repair (TC-NER). Several epigenetic modifications were also found to be involved at Th1 gene locus which are responsible for active/repressive marks of particular genes. By demonstrating WASp as a physiologic regulator of programmed versus unprogrammed R-loops, we suggest that the transcriptional role of WASp in vivo extends also to prevent transcription-linked DNA damage during malignancy and through modification of epigenetic dysregulations. Our findings present a provocative possibility of resetting R-loops as a therapeutic intervention to correct both immune deficiency and malignancy in T-cell acute lymphoblastic leukemia patients and a novel role of WASp in the epigenetic regulation of T helper cell differentiation in T-ALL patients, anticipating WASp's requirement for the suppression of T-ALL progression.
2024-05-07 | THE POTENTIAL OF HUMAN PLASMA AND HUMAN BLOOD PRODUCTS FOR IMMUNE PROTECTION
Intravenous Immunoglobulin (IVIg) were used for the first time at the late seventies for treatment of patient with primary and secondary immunodeficiencies. Тhe first observations opened a wide field for basic and clinical research leading to a rapidly expanding use of IVIg for the treatment of patients with multiple diseases. The immunoglobulin preparations contain large amount of intact form of IgG molecules with comparable values of subclasses as in native plasma. Тhose properties account for the normal half-life of injected immunoglobulin of three weeks, and its ability to react normal with the complement components and with the specific Fcγ-receptors on the surface of phagocytes and lymphocytes. IVIg is produced from plasma pules from several thousand donors, which leads to wide spectre of variable regions of IgG molecules in the product. Some of the antibodies in the product can recognize bacterial, virus and fungal antigens are essential in replacement therapy in patients with antibody deficiency. А good understanding of the molecular and cellular basis of the immunoregulatory actions of intravenous immunoglobulin preparations is important for optimizing their use in inflammatory diseases for conducting new clinical observations.
cell therapies
2026-07-03 | Atypical Wiskott-Aldrich syndrome presenting with normal platelet volume and end-stage renal disease: from misdiagnosis as ITP to combined transplantation.
We report a 30-year-old male with a novel WAS mutation (c.252C > A, p.F84L) who was misdiagnosed with immune thrombocytopenia (ITP) for years. Despite persistent thrombocytopenia, his mean platelet volume remained normal, an atypical feature of Wiskott-Aldrich syndrome (WAS). His course was complicated by stage-5 chronic kidney disease, renal anemia, IgA nephropathy, and recurrent infections. Laboratory tests consistently showed low lymphocyte counts and reduced WAS protein (WASp) levels. After confirming WAS, the original plan of kidney transplantation alone was changed to combined hematopoietic stem cell and kidney transplantation to restore immunity and reduce graft failure risk. This case highlights that WAS can present with normal platelet volume; thus, WAS should be considered in patients with unexplained chronic kidney disease, recurrent infections, and poor ITP therapy response, even without typical microthrombocytopenia.
2025-04-10 | How I treat Wiskott-Aldrich syndrome.
Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder, characterized by thrombocytopenia, eczema, recurrent infections, autoimmunity, and malignancy. Here, we discuss current conservative and definitive approaches to treating WAS, based on recently published evidence. Disease severity in WAS is highly variable. Recent studies confirm that the probability of disease progression depends on the type of genetic variant, supporting early diagnosis and tailored treatment strategies. Milder cases, historically termed X-linked thrombocytopenia (XLT), received supportive care, whereas severe cases were referred for standard allogeneic hematopoietic cell transplantation (HCT) or gene therapy (GT) in clinical trials. Advances in HCT and GT, together with recent knowledge that even patients with XLT are at risk for severe immune complications, suggest that most young patients with WAS should be offered a potentially curative approach at diagnosis. Older patients with a small subset of milder variants may be treated conservatively unless they develop life-threatening autoimmune or malignant complications; regular monitoring and proactive management are critical to preventing irreversible complications. We recommend discontinuing the term XLT as it implies a mild and uncomplicated disease, which is not the norm, and instead tailor treatment for all patients with WAS to their individual genetic profile, disease severity, and clinical course.
2024-10-26 | Pathophysiology of Congenital High Production of IgE and Its Consequences: A Narrative Review Uncovering a Neglected Setting of Disorders.
Elevated serum IgE levels serve as a critical marker for uncovering hidden immunological disorders, particularly inborn errors of immunity (IEIs), which are often misdiagnosed as common allergic conditions. IgE, while typically associated with allergic diseases, plays a significant role in immune defense, especially against parasitic infections. However, extremely high levels of IgE can indicate more severe conditions, such as Hyper-IgE syndromes (HIES) and disorders with similar features, including Omenn syndrome, Wiskott-Aldrich syndrome, and IPEX syndrome. Novel insights into the genetic mutations responsible for these conditions highlight their impact on immune regulation and the resulting clinical features, including recurrent infections, eczema, and elevated IgE. This narrative review uniquely integrates recent advances in the genetic understanding of IEIs and discusses how these findings impact both diagnosis and treatment. Additionally, emerging therapeutic strategies, such as hematopoietic stem cell transplantation (HSCT) and gene therapies, are explored, underscoring the potential for personalized treatment approaches. Emphasizing the need for precise diagnosis and tailored interventions aims to enhance patient outcomes and improve the quality of care for those with elevated IgE levels and associated immunological disorders.
2024-09-25 | Hematopoietic cell transplantation for inborn errors of immunity: an update on approaches, outcomes and innovations.
Allogeneic hematopoietic cell transplantation (HCT) is a curative option for many for inborn errors of immunity (IEI). This review highlights recent progress in the field of HCT for IEI. Alternative donor transplantation continues to expand donor options for patients with IEI. Reduced intensity and reduced toxicity conditioning approaches are being investigated and optimized. Immunomodulatory bridging therapies are yielding impressive progress in outcomes for primary immune regulatory disorders (PIRD) but require further study in prospective trials. Single-institution, multicenter and consortium studies have improved our understanding of factors that affect overall outcomes in IEI and outcomes in Wiskott-Aldrich syndrome (WAS), chronic granulomatous disease (CGD) and PIRD in particular. Data show that second HCT offers a viable chance of cure to some IEI patients. Late effects in IEI HCT survivors are being better characterized. Preclinical studies of chemo(radiation)-free HCT strategies hold promise for decreasing HCT toxicity. Improvements in our understanding of HCT donor choice, conditioning regimen, immunomodulatory bridging therapies, diagnostic and post-HCT surveillance testing and late effects continue to yield advancements in the field of HCT for IEI.
2024-02-01 | Haploidentical bone marrow transplantation in a pediatric patient with Wiskott-Aldrich syndrome. A case report
Wiskott-Aldrich syndrome (WAS) is an X-linked genetic disorder caused by mutations in the gene that encodes the Wiskott-Aldrich syndrome protein (WASp).Here, we report the clinical case of an 18-month-old boy diagnosed with Wiskott-Aldrich syndrome, who did not have an HLA-matched related or unrelated donor and was treated successfully with a hematopoietic stem cell transplant (HSCT) from a haploidentical family donor.Graft-versus-host disease (GvHD) prophylaxis included post-transplant cyclophosphamide (PT-Cy).At day +30, the peripheral blood-nucleated cell chimerism was 100% and the WAS protein had a normal expression.Currently, at month 32 post-transplant, the patient has hematological and immune reconstitution and complete donor chimerism without evidence of GvHD.HSCT with PT-Cy was a feasible and safe option for this patient with WAS, in which an HLA matched donor was not available.
gene therapies
2026-07-25 | Gene therapy approaches for inborn errors of immunity: from bench to bedside.
Inborn errors of immunity (IEI) are rare genetic defects that disrupt immune function, often resulting in life-threatening infections, malignancies, and immune dysregulation. Allogeneic hematopoietic stem cell transplantation (HSCT), a curative option for some diagnoses, is limited by donor availability and the risks of graft-versus-host disease. This review explores the 30-year evolution of autologous gene therapy as a vital alternative to allogeneic HSCT for IEIs. Literature search using PubMed for gene therapy for IEI in the last 20 years. We trace the transition from early gamma-retroviral gene addition, which successfully restored immunity in severe combined immunodeficiency (SCID) but carried high risks of insertional mutagenesis and leukemogenesis, to the adoption of safer self-inactivating lentiviral vectors. The field is rapidly advancing beyond viral gene addition toward highly precise gene‑editing technologies, including CRISPR/Cas9 and base/prime editing, which offer targeted correction with minimized genotoxicity. Recent milestones in diseases such as Wiskott -Aldrich syndrome (WAS) and chronic granulomatous disease (CGD) highlight enormous scientific success, yet significant barriers to accessibility, manufacturing, and affordability remain. Overcoming this requires innovative regulatory frameworks and collaborative funding models. Streamlining development and ensuring equitable access are essential next steps to establishing gene therapy as a safe alternative.
2026-07-06 | The spectrum of bleeding in Wiskott-Aldrich syndrome: a systematic review and meta-analysis of incidence and mortality
Background Bleeding is the predominant clinical manifestation and one of the leading causes of death of Wiskott-Aldrich syndrome (WAS). However, significant discrepancies in reported bleeding phenotypes persist. Objective This systematic review and meta-analysis aim to provide a comprehensive characterization of the bleeding phenotype and elucidate the resultant mortality burden among patients with WAS. Methods Observational studies reporting either the cumulative incidence of bleeding manifestations or the occurrence of fatal hemorrhagic events in patients with WAS were included. The Joanna Briggs Institute critical appraisal tool was used to assess the risk of bias. A generalized linear mixed model with a binomial-normal distribution was employed for the meta-analysis. Subgroup analyses, stratified by clinical stage at data collection, and meta-regression analyses were conducted to explore heterogeneity. Results A total of 40 studies involving 1865 patients were identified. The pooled cumulative incidences of overall and site-specific bleeding (excluding gastrointestinal bleeding), increased significantly from disease onset to diagnosis and through to the end of follow-up. At the end of follow-up, the pooled cumulative incidence of multisystem bleeding and severe bleeding was 57% (95% CI 41-72) and 19% (95% CI 12-28), respectively. Both sample size and proportion of patients with a WAS score of 5 were associated with cumulative incidence of severe bleeding at the end of follow-up ( p = 0.0042 and 0.0423, respectively). The cause-specific mortality rate from hemorrhage was 9.3% (95% CI: 6.1-13.8; I 2 = 0%) in non-curatively treated patients and 1.0% (95% CI: 0.4-2.4; I 2 = 0%) in curatively treated patients. Curative treatment was associated with a significantly lower risk of fatal hemorrhage compared to non-curative treatment (RR = 0.07, 95% CI 0.01-0.49). The proportional mortality ratio due to hemorrhage was 30% (95% CI 22-39) in non-curatively treated patients. Fatal hemorrhages were highly skewed toward early childhood (median age-at-death: 22 months), with intracranial hemorrhage being the predominant cause of death (76.1%). Conclusions Bleeding complications are nearly universal and progressive in patients with WAS. Given that most fatal hemorrhages occur in early childhood and curative treatment significantly mitigates this risk, prompt implementation of such therapy is imperative. Systematic review registration https://www.crd.york.ac.uk/prospero/ , identifier CRD420261277891.
2026-03-11 | FDA must regulate stem cell therapies to mitigate risks to patients and the public
In December 2025, the US Food and Drug Administration's (FDA's) Center for Biologics Evaluation and Review (CBER) approved a gene-based stem cell therapy for Wiskott-Aldrich syndrome, a rare and life-threatening genetic disease.This decision was appropriately based on data from two clinical studies that demonstrated a clinical benefit.Unfortunately, this standard of evidence, and FDA approval itself, are not the norm for many stem cell therapies.Instead, hundreds, if not thousands, of clinics have made unproven and unapproved stem cell treatments widely available to treat everything from common sports injuries to neurological diseases.Officials from the FDA and other federal agencies have tried to stop this potentially dangerous trade.As part of those efforts, the FDA filed two lawsuits in 2018 against clinics involved in the online promotion of unapproved stem cell therapies.After years of court filings and appeals, the agency won an important court case in late 2024 that confirmed the FDA's power to regulate unproven stem cell therapies.In October 2025, the US Supreme Court declined to reconsider the decision, meaning that after seven years, the FDA had confirmed its regulatory authority over a burgeoning online industry.That's good news for proponents of evidence-based medicine.But for how long will this position hold?This may depend in significant part on the current leadership at the Department of Health and Human Services (HHS), which sits above the FDA.Thus far, the signs are not good.Since Congress' February 2025 confirmation of Robert F. Kennedy, Jr. (RFK Jr.) as Secretary of HHS, changes in the FDA's senior officials and policy priorities suggest that the FDA may back away from exercising the authority to regulate this important field, despite its seven-year battle to do so.Here, we highlight the changes that the current Administration might consider for FDA
2025-12-11 | EMA – First gene therapy to treat rare disease Wiskott-Aldrich syndrome
EMA has recommended granting a marketing authorisation in the European Union (EU) for Waskyra (etuvetidigene autotemcel) to treat people aged 6 months and older with Wiskott-Aldrich syndrome (WAS) who have a mutation in the WAS gene. Waskyra is used to treat patients for whom a haematopoietic stem cell transplantation (HSCT) is appropriate, but for whom no suitable stem cell donor is available. Wiskott-Aldrich syndrome is a rare, inherited disease, seen almost exclusively in males, that affe...
2025-11-03 | National temporal trends and demographic disparities in primary immunodeficiency-related mortality in the United States, 1999–2024
Abstract Background: Primary immunodeficiency disorders (PIDs) comprise hundreds of rare, genetically defined conditions that confer susceptibility to infection, autoimmunity, and early death. Although therapeutic advances and neonatal screening have improved outcomes, contemporary population-level evidence on PID mortality and equity is limited. This study aimed to quantify national trends in PID-related mortality and to characterize disparities by race, sex, and urbanization. Methods: We extracted data from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) Multiple Cause-of-Death (MCD) database, identifying all U.S. deaths from January 1, 1999, through December 31, 2024, where the cause of death had ICD-10 codes D80–D84 listed as MCD. This spectrum encompasses predominantly antibody deficiencies (D80: hereditary or nonfamilial hypogammaglobulinemia, selective IgA/IgG/IgM deficiencies, hyper-IgM syndromes, and related entities), combined immunodeficiencies including classic severe combined immunodeficiency and its genetic variants (D81), syndromic or major-defect-associated immunodeficiencies such as Wiskott-Aldrich, DiGeorge, and hyper-IgE syndromes (D82), common variable immunodeficiency and its sub phenotypes (D83), and other specified or unspecified immunodeficiencies such as LFA-1 or complement defects (D84). Age-adjusted mortality rates (AAMRs) per 1,000,000 population were calculated by direct standardization to the 2000 U.S. population. Joinpoint regression generated annual percent change (APC) and average annual percent change (AAPC) for the overall population and strata defined by sex and race/ethnicity (non-Hispanic Black, non-Hispanic White, Hispanic). Urban–rural residence was examined with the 2013 NCHS Urban–Rural Classification, which CDC WONDER provides only through 2020; therefore, urbanization analyses cover 1999–2020. Mortality data for 2024 are provisional. Results: During the 26-year interval between 1999 and 2024, 27,616 PID-related deaths occurred. The overall AAMR declined from 4.85 in 1999 to 3.15 in 2024, corresponding to an AAPC of –1.33 %. Throughout the study, men retained higher AAMR than women (2024: 3.4 vs 2.9), yet both sexes showed significant declines (AAPC –1.9 % and –1.1 %, respectively). Initially, non-Hispanic Black individuals faced the highest burden, with an AAMR of (11.2) compared to (4.3) among non-Hispanic Whites and 3.8 among Hispanics. Remarkably, Blacks exhibited the steepest sustained improvement (AAPC –4.9%), such that by 2024 their mortality rate had fallen to 3.7, only marginally higher than Whites (3.4) and Hispanics (3.0). The Black-to-White gap narrowed from 2.6-fold to approximately 1.1-fold. From 1999 to 2020, rural residents consistently had higher mortality rates than urban residents; although both groups improved, the decline plateaued after 2015, with an AAPC of -2.45% and -3.36%, respectively. Conclusions: National PID-related mortality has decreased significantly since 1999, mainly due to rapid declines among non-Hispanic Black Americans, nearly eliminating long-standing racial disparities. Ongoing higher mortality rates among males and rural communities, along with a recent slowdown in progress, highlight the need for more access to newborn screening, curative treatments, and specialized care for all populations.
other
2025-11-21 | Dupilumab for atopic manifestations in pediatric patients with inborn errors of immunity: efficacy and safety in a genetically diverse cohort
Background Inborn Errors of Immunity (IEI) are monogenic disorders that predispose patients to infections, autoimmunity, atopy, and malignancies. Severe Th2-driven atopic dermatitis and asthma are common in several IEIs, including DOCK8 deficiency, STAT3 loss-of-function, and Wiskott–Aldrich syndrome, often refractory to conventional therapies. Dupilumab, a monoclonal antibody targeting IL-4Rα, has shown promise in managing recalcitrant atopic dermatitis and asthma, but data in immunocompromised pediatric populations remain limited. Methods We conducted a single-center, retrospective observational cohort study with prospective follow-up of ten pediatric patients with genetically confirmed IEI and atopic manifestations. Patients received subcutaneous dupilumab (300 mg every 4 weeks for atopic dermatitis; every 2 weeks for severe asthma). Outcomes were assessed using the Eczema Area and Severity Index (EASI), Dermatology Life Quality Index (DLQI), Childhood Asthma Control Test (C-ACT), eosinophil counts, and infection frequency across four time points (baseline, 6 months, 12 months, >18 months). Results The cohort included ten patients (6 males, 4 females) with mutations in DOCK8 (n=5), CARD11 (n=2), STAT3 LOF (n=1), ADA (n=1), and PEPD (n=1). Of ten patients, nine received dupilumab for atopic dermatitis. Baseline EASI and DLQI scores were 34.33 and 25.0, respectively. Following dupilumab therapy, mean EASI decreased to 2.67 (p<0.001) and DLQI improved to 2.67 (p<0.001), with sustained response observed over 18 months. Peripheral eosinophil counts declined from 2.0×10 9 /L to 0.45×10 9 /L (p<0.001). One patient with severe asthma achieved C-ACT improvement from 10 to 26 with no subsequent exacerbations. Treatment was well-tolerated, with only mild conjunctivitis or transient hypereosinophilia reported. Notably, skin infections resolved, and no systemic or opportunistic infections were observed. Conclusion Dupilumab is a safe and highly effective therapeutic option for pediatric patients with IEI-associated atopic manifestations, improving clinical outcomes, quality of life, and infection profile while preserving immune function. These findings support broader application of dupilumab in patients with IEI and warrant further investigation in larger, multicenter studies.
2025-11-03 | The clinical observation of treating autoimmune cytopenias after allogeneic hematopoietic stem cell transplantation in children by immunoinduction therapy
Abstract This retrospective study explored safety and efficacy of immunoinduction methods such as Immunosuppressants are reduced and discontinued, with or without PD1 inhibitors, or donor lymphocyte reinfusion (DLI) in the treatment of autoimmune cytopenias (AIC) after allogeneic hematopoietic stem cell transplantation. The clinical data of 20 children admitted to Beijing JingDu Children's Hospital from January 2019 to May 2025 with AIHA (10 cases), ITP (7 cases), and Evans syndrome (3 cases) after allogeneic hematopoietic stem cell transplantation were retrospectively analyzed (5-AA; 4-chronic granulomatous disease; 3-HLH; 2-Wiskott-Aldrich syndrome; 1- Congenital neutropenia; 1-ALL; 1-pyruvate kinase deficiency anemia; 1-Thalassemia; 1-Mucopolysaccharidosis type I; 1-Mucopolysaccharidosis type Ⅱ). Among the 20 cases, 7 cases had mixed chimerism and 13 cases had complete chimerism at the onset of AICs. In all cases, corticosteroids were treated with or without IVIG and rituximab for 1 to 5 weeks, and then Immunosuppressants such as cyclosporine or tacrolimus etc, are reduced and discontinued, combined with or without PD1 inhibitors and DLI were used to treat AICs. The median age of AICs in 20 children was 4 (range:1.25-17) years; median time to development of AICs: 9 (range:4-68) months after transplantation; the median number of recurrent episodes of AICs was 2 (1-5) times. ATG was used in the conditioning regimen of 20 children. Among the 20 children, 5 children cured after stopping immunosuppressants, and 15 children were cured after stopping immunosuppressants combined with PD1 inhibitors or DLI, the average duration of treatment is 2 (0.5-6) months. Among the 20 children, 11 children had grade I~II skin or liver rejection, which were controlled after topical medication or short-term low-dose immunosuppressant therapy. At a median follow-up of 20(2-62) months after discontinuation of treatment, none of the children had recurrence. The immunoinduction therapy of AICs after allogeneic hematopoietic stem cell transplantation is safe and effective.
2025-10-20 | Atopic dermatitis in inborn errors of immunity: at the interface of immunodeficiency and immune dysregulation.
Inborn errors of immunity (IEI) encompass a broad spectrum of immunodeficiency disorders characterized by variability in genetic background, individual immunophenotype, and clinical manifestations with organ-specific immunopathology and immune dysregulation in the form of atopy, autoimmunity, polyclonal lymphoproliferation, and malignancy. With the ever-expanding insight in the pathophysiology of IEI, atopy may be perceived as an integral part and even a hallmark of IEI diseases. This review is aimed at gathering, delineating, and summarizing the immunogenetic underpinnings of IEI diseases accompanied by atopic dermatitis. Particular emphasis is laid on syndromes connected with atopy, such as hyper-IgE syndromes, Omenn syndrome, immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, Netherton syndrome, Wiskott-Aldrich syndrome, and atypical complete DiGeorge syndrome. Therefore, atopic dermatitis proved not to be a sole disease, but rather a warning sign of multiple pediatric monogenic immunodeficiency disorders. Surpassing from the era of clinical and immunological diagnosis to the era of immunogenetics and the integrated "omics" approach highlighted the complex and heterogeneous immunopathology of atopic dermatitis. It also paved the way for patient-tailored immunotherapies with monoclonal antibodies and small molecules targeted at suppressing atopic inflammatory processes and improving disease-associated outcomes.
2025-02-25 | Dupilumab successfully controlled eczema in Wiskott-Aldrich Syndrome over 52 weeks.
Wiskott-Aldrich syndrome (WAS) is a rare genetic disorder characterized by immunodeficiency, thrombocytopenia, and eczema. The Management of eczema remains still a major clinical challenge. We present a rare case of eczema associated with WAS in an 8-year-old boy whose lesions significantly improve after a 4-week treatment of dupilumab, a interleukin(IL)-4α receptor monoclonal antibody. Although eczema relapsed after stopping dupilumab, and alleviated after dupilumab was resumed. Finally, the Eczema Area and Severity Index (EASI) score decreased to less than 7 after the patient receive dupilumab 300 mg every 4 weeks over 52 weeks. This case suggests that dupilumab is a promising therapy alternative for patient with eczema in WAS.
2024-07-26 | Interleukin-1 blockade in patients with Wiskott-Aldrich syndrome: a retrospective multinational case series.
Up to 70% of patients with Wiskott-Aldrich syndrome (WAS) develop autoimmune and inflammatory manifestations. Dysregulation of interleukin 1 (IL-1) may be involved in their pathogenesis, yet there is little evidence on treatment with anti-IL-1 agents in these patients. We conducted a multicenter retrospective analysis of 9 patients with WAS treated with anti-IL-1 agents (anakinra or canakinumab). All patients had prominent inflammatory manifestations, including systemic, cutaneous, articular, and intestinal symptoms; 3 patients presented with a severe systemic inflammatory syndrome since the first months of life. Corticosteroid therapy was associated with partial or no response, whereas treatment with anakinra or canakinumab resulted in prompt, often dramatic, responses in all patients, allowing bridging to gene therapy (4 patients) or hematopoietic stem cell transplantation (HSCT; 5 patients). Treatment was overall well tolerated. Low donor myeloid chimerism developed in 4 patients after HSCT and was associated with the appearance or the recurrence of inflammatory manifestations. A second HSCT was performed in 2 patients, achieving full-donor chimerism and resolution of inflammatory manifestation, whereas the other 2 patients were treated with prolonged therapy with anti-IL-1 agents. Our experience demonstrates that some inflammatory manifestations of WAS are dependent on IL-1 and respond well to its pharmacologic blockade.
small molecules
2026-09-17 | Parthenolide boosts megakaryocyte maturation and restores platelet responses in Wiskott–Aldrich syndrome
Abstract Wiskott-Aldrich syndrome (WAS) is an inborn error of immunity with a broad disease spectrum, classified into class I (late onset) or II (early onset) variants. Thrombocytopenia and small platelets are the most consistent findings among patients, difficult to treat and related to development of autoimmunity. To identify new treatment options for thrombocytopenia in WAS, we developed a FACS-based screening for drug repurposing. We identified parthenolide as a lead small molecule that increased WASp abundance in cells with residual WASp expression. Using the megakaryocytic MEG-01 cells, gene edited to express WAS class I and II genetic variants, parthenolide induced megakaryocyte maturation as evident by upregulation of CD61, increased cell size and complexity, increased phosphorylation of ERK1/2, and higher DNA ploidy. We generated a new mouse model harboring a WAS class I missense variant WASp-R88C, corresponding to human WASp-R86C, with reduced expression of WASp. WASp-R88C mice had lower numbers of platelets compared to WT mice. Bone marrow-derived WASp-R88C and WASp-KO megakaryocytes, differentiated in the presence of parthenolide derivative, DMAPT, showed increased ploidy and upregulation of the maturation markers CD61, CD41 and CD42d, resulting in improved platelet production in vitro . Treatment with parthenolide derivative, DMAPT, led to increased platelet numbers in vivo in WASp-R88C mice and dampened the hyperactivation of WAS patient platelets by reducing thrombin-induced CD62P exposure after activation. The identification of parthenolide offers a promising therapeutic approach for WAS patients who are unresponsive or unsuitable for definitive therapies. Key points A FACS-based drug screen using degradation-prone class I WAS variants identifies parthenolide/DMAPT as a candidate that enhances megakaryocyte maturation and platelet production in vitro . Parthenolide/DMAPT thrombopoietic activity increases platelet production in vivo and restores improves cytoskeletal remodeling of WAS megakaryocytes and platelets.
2026-06-22 | An asymptomatic WASF1 truncation reveals pathogenic mechanism and therapeutic strategy for neurodevelopmental disorders.
Wiskott-Aldrich syndrome protein family member 1 (WASF1) truncating variants, such as c.1516C>T (p.Arg506Ter), are established causes of neurodevelopmental disorders (NDDs), but their underlying pathogenic mechanism remains debated. This study aimed to clarify the disease mechanism and identify potential therapeutic leads. We characterized a novel, asymptomatic WASF1 truncating variant (c.873delA) and compared its clinical and molecular consequences with those of the known pathogenic c.1516C>T variant. To target the likely pathogenic mutant protein, we performed high‑throughput virtual screening of the ZINC20 database. Despite a similar reduction in wild‑type protein levels, the c.873delA variant did not cause neurological symptoms, in contrast to c.1516C>T. This observation supports a dominant‑negative, gain‑of‑function, or altered protein function mechanism rather than simple haploinsufficiency; however, the precise mechanism could not be definitively resolved from the available genetic and protein expression data. Virtual screening identified ZINC000101023849 as a high‑affinity lead compound with favorable drug‑like properties. This study provides key evidence that WASF1‑related NDDs likely arise from a non‑haploinsufficiency mechanism and delivers a promising chemical lead for targeted therapy development. Further studies are needed to confirm the exact pathogenic mechanism and to validate the therapeutic potential of the identified compound.
2026-06-04 | The Forefront of Hematopoietic Stem Cell Transplantation: Focus on Inborn Errors of Immunity
Approximately 100 allogeneic hematopoietic stem cell transplantation (HSCT) procedures are performed for nonmalignant diseases in Japan annually. Inborn errors of immunity (IEIs) account for approximately one-third of patients with nonmalignant diseases (NMDs), which mainly comprises chronic granulomatous disease, severe combined immunodeficiency, Wiskott-Aldrich syndrome, and hyper IgM syndrome. Unlike hematological malignancies, no tumor cells do exist to be elucidated in the setting of allogeneic hematopoietic cell transplantation (HCT) for IEIs; therefore, intensive conditioning regimens, or rapid reduction or discontinuation of immunosuppressive agents to enhance alloreactive anti-tumor effect, is not required. However, because these patients do not generally receive pre-HCT chemotherapy, they can occasionally show sufficient immune response to reject donor cells, leading to higher risks of graft failure or mixed chimerism. Furthermore, patients with preexisting infection and organ failure due to the underlying disease itself or long-term use of immunosuppressive agents have a higher risk of severe early transplant-related adverse effects. These fundamental differences might affect the development of original transplant strategy for IEIs. Recent rapid advancements in transplant strategy have a great impact on allogeneic HSCT. Particularly, introduction of novel graft versus host disease (GVHD) prophylaxis, such as post-transplant cyclophosphamide and anti-CD52 antibody alemtuzumab, has enabled safe allogeneic HSCTs from alternative donors. Due to relatively higher post-transplant survival rates, it is essential to transplantation methods that ensure high survival rates while reducing the risk of early and late post-transplant complications. Therefore, there is a need for a scoring system for defining conditioning intensity and comprehensive assessments of late complications. In this session, I will provide an overview of the current status and future challenges of allogeneic HSCT for IEI, mainly based on the results of retrospective studies using a nationwide database established by the Japanese Data Center for Hematopoietic Cell Transplantation.
2026-04-08 | Pharmacological activation of WASp potentiates macrophage phagocytosis and enhances ibrutinib efficacy against mouse models of brain tumors.
Both primary and metastatic brain malignancies are fatal and highly infiltrated with tumor-associated macrophages (TAMs). Enhancing the phagocytosis of neoplastic cells by TAMs is pivotal for slowing tumor growth. Great endeavors have been made to develop tyrosine kinase inhibitors (TKIs) for brain malignancies, yet whether tumor-targeting TKIs affect the phagocytic capacity of TAMs remains largely unknown. In this preclinical study, we report that repurposing ibrutinib, a blood-brain barrier-penetrable TKI, effectively suppresses the growth of several primary and metastatic brain tumors highly expressing Bruton's tyrosine kinase (BTK) or bone marrow X-linked nonreceptor tyrosine kinase (BMX) but concurrently dampens the TAM phagocytic function. Mechanistically, BTK, which is activated in TAMs, interacts with and phosphorylates Wiskott-Aldrich syndrome protein (WASp) to organize the actin cytoskeleton, which is imperative for phagocytosis. Ibrutinib treatment disrupts BTK-mediated WASp activation, thereby compromising TAM phagocytic efficacy. Pharmacological activation of WASp by its selective small-molecular activator EG-011 restores the ibrutinib-impaired TAM engulfment of tumor cells and effectively improves ibrutinib efficacy in mice bearing glioblastomas, primary central nervous system lymphomas, and lung carcinoma brain metastases. Furthermore, elevated expression of phosphorylated BTK or phosphorylated WASp in TAMs correlates with an increased phagocytic TAM subset identified by single-cell RNA sequencing and correlates with prolonged patient survival in a cohort with glioblastoma. Our preclinical study highlights the necessity of evaluating the on-target, off-tumor attack of TAMs during TKI administration and provides a proof of concept for reinvigorating the TAM phagocytic function to achieve additional clinical benefit.
2026-04-03 | Abstract 4512: WASP activation by BM011 triggers mitochondrial collapse and aldolase-dependent glycolytic vulnerability in lymphoma.
Abstract Background. BM011 is the first-in-class WASP (Wiskott-Aldrich Syndrome Protein) activator (Spriano et al, 2024). WASP regulates cytoskeletal remodeling, immune synapse formation, vesicle trafficking, and mechano-metabolic coupling. Aberrant actin dynamics and rewiring of the WASP pathway contribute to proliferation, metabolic flexibility, and stress resistance in lymphomas and other cancers. Here, we investigated the mechanism of action of BM011 by combining transcriptomics, proteomics, and a genome-wide CRISPR-Cas9 knockout screen in lymphoma cells treated with the compound. Methods. JEKO1 mantle cell lymphoma cells were treated with BM011 for 8h and analyzed by RNA-Seq and mass spectrometry (MS). A genome-wide CRISPR-Cas9 knockout screen was conducted following 14-day exposure to BM011. Results. Proteomics revealed a strong downregulation of mitochondrial import and respiratory chain proteins in BM011-treated cells, while many RNAs coding for the same molecules were upregulated, consistent with an attempt to compensate for mitochondrial stress. Similarly, ribosomal proteins decreased, while ribosomal transcripts increased, suggesting a proteotoxic stress response and a translational offset. Stress-response genes (e.g., HSPA family), cytoskeleton, and apoptotic pathways were strongly induced, indicating proteotoxic pressure, cytoskeleton remodeling, and apoptosis induction following cytoskeletal forcing. At the genetic screen, the loss of many mitochondrial respiratory chain genes sensitized cells to BM011, confirming their importance in mitigating BM011-induced mitochondrial collapse. In contrast, the knockout of FUNDC2 and TIMM23, not part of the mitochondrial respiratory chain, conferred resistance, likely due to the interruption of mitochondrial quality control and decreased apoptosis upon BM011 treatment. The genetic screen also revealed a divergent vulnerability to glycolysis. Knockout of genes coding for enzymes of the upper glycolytic process (HK2, PFKM, PFKL, GPI, PFKFB3) conferred resistance, while knockout of genes coding for proteins in the lower part of glycolysis (PGK1, ENO1, PKM, PFKFB4) increased sensitivity. This pointed to aldolase and the fructose-1,6-bisphosphate node as a critical metabolic point. Aldolase can indeed bind to F-actin and WASP, inhibiting actin polymerization. Additionally, an excess of fructose-1,6-bisphosphate (F16bP) inhibits aldolase binding to F-actin. We proved that F16bP supplementation or aldolase inhibition increased the sensitivity of BM011 in otherwise resistant lymphoma cells. Conclusion. BM011-driven activation of WASP induces cytoskeletal stress, mitochondrial import failure, and a proteotoxic response, with upper-glycolysis and aldolase acting as a metabolic safety valve. These reveal druggable metabolic-cytoskeletal vulnerabilities in lymphoma. Citation Format: Filippo Spriano, Luciano Cascione, Stephen Croke, Digvijay Gahtory, Maurits van den Nieuwboer, Francesco Bertoni. WASP activation by BM011 triggers mitochondrial collapse and aldolase-dependent glycolytic vulnerability in lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4512.
proteins
2025-08-21 | Mechanistic understanding of Wiskott-Aldrich syndrome protein (WASp)-mediated epigenetic regulation of T helper cell differentiation in acute leukemia.
Wiskott-Aldrich syndrome protein (WASp) is exclusively expressed in hematopoietic cells, yet its role in leukemia remains poorly defined. This study investigates the epigenetic regulation of key immune genes by T helper (TH) cell transcription factors. Human CD4⁺ T cells from healthy donors and patients with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) were transfected with control CRISPR (CO), WASp knockout (WKO), and WASp overexpression (WOE) plasmids. Flow cytometry confirmed intracellular WASp staining in CO, WKO, and WOE CD4⁺ T cells. WOE leads to elevated mRNA levels of TH1-associated transcription factors, such as TBX21 and IFNγ. Notably, TBX21 enrichment increased significantly in WOE cells, while no such enrichment was observed for GATA3, RORC, or FOXP3. In addition, aberrant accumulation of R-loops at key gene loci, including TBX21, STAT1, ATM, and H2AFX, was prominently observed in WKO cells but not in WOE conditions. DNA methylation increased WKO cells but m6A levels were elevated under WOE conditions. Immunofluorescence analysis revealed much higher WASp expression in WOE but increased γH2A.X fluorescence in WKO. We found WASp stably interacts with the STAT1 binding region in the TBX21 promoter by molecular docking studies. Nitric oxide, reactive oxygen species, and glutathione levels were higher in WKO cells, while lactate dehydrogenase levels were increased in WOE samples. These findings collectively imply that WOE in acute leukemia promotes TH1 cell activity in a significant manner through epigenetic regulation and could be a potential therapeutic target. The online version contains supplementary material available at 10.1007/s13205-025-04474-4.
2025-03-06 | Molecular mechanism of Arp2/3 complex activation by nucleation-promoting factors and an actin monomer.
Arp (actin-related protein) 2/3 complex nucleates actin filament branches on the sides of preexisting actin filaments during cell and organelle movements. We used computer simulations of mammalian Arp2/3 complex to address fundamental questions about the mechanism. Metadynamics and umbrella free energy sampling simulations of the pathway revealed that a clash between the D-loop of Arp2 and Arp3 produces an energy barrier of 20 ± 6 kcal/mol between the inactive splayed and active short-pitch conformations of Arp2/3 complex. Atomistic molecular dynamics simulations showed that binding the CA motif of the nucleation-promoting factor Neuronal Wiskott-Aldrich Syndrome Protein (N-WASp) to inactive, splayed Arp2/3 complex shifts it toward the short-pitch active conformation and opens a binding site for an actin monomer on Arp3. Other simulations showed that this actin monomer stabilizes a transition state of Arp2/3 complex. These observations together with prior experimental work provide insights required to propose a physically grounded pathway for actin filament branch formation.
2024-11-17 | Wiskott-Aldrich syndrome protein maintains regulatory T cell tolerance by modulating their surface IL-2 receptor levels.
Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency condition caused by ablation of functional WAS protein (WASP) expression, and associated with susceptibility to infections, eczema, and autoimmunity. Regulatory T cell (Treg) defects are an important cause of autoimmunity in WAS. Currently, the mechanisms underlying cytoskeleton involvement in Treg-regulated autoimmunity remain unclear, and WAS is an excellent model for investigation of this question. Here, we examined patients with WAS and WASP knockout (WASp-/-) mice to uncover a new mechanism involving the actin nucleation promoting factor, WASP, in regulating Treg tolerance by modulating their surface IL-2 receptor (IL-2R) levels. Surface expression levels of IL-2R and its downstream signaling molecules, phosphoinositide 3-kinase/pSTAT5, are decreased in WASp-/- Tregs. Low dosage IL-2 combined with anti-IL-2 monoclonal antibody (IL2 complex) treatment can compensate for Treg deficiency in WAS in vitro and in vivo. Moreover, IL2 complex treatment relieved autoimmune colitis in WASp-/- mice. Reduced surface IL-2R is primarily caused by elevated IL-2R internalization and degradation, and lysosomal and endosomal genes associated with these processes are upregulated in WASp-/- Tregs. Finally, spatiotemporal analysis of dynamin and Neural Wiskott Aldrich Syndrome Protein (N-WASP) recruitment, by generating lipid bilayers and total internal reflection fluorescence microscopy, showed that WASP deficiency promoted IL-2R internalization and degradation by enhancing N-WASP activation. Consistently, N-WASP inhibition in Tregs using wiskostatin reduced IL-2R internalization. Together, our results reveal a novel intrinsic role of WASP in regulation of surface IL-2R dynamics in Tregs, highlighting a potential new therapeutic approach for autoimmune diseases.
2024-05-17 | Wiskott Aldrich syndrome protein (WASp)-deficient Th1 cells promote R-loop-driven transcriptional insufficiency and transcription-coupled nucleotide excision repair factor (TC-NER)-driven genome-instability in the pathogenesis of T cell acute lymphoblastic leukemia.
T-ALL is an aggressive hematological tumor that develops as the result of a multi-step oncogenic process which causes expansion of hematopoietic progenitors that are primed for T cell development to undergo malignant transformation and growth. Even though first-line therapy has a significant response rate, 40% of adult patients and 20% of pediatric patients will relapse. Therefore, there is an unmet need for treatment for relapsed/refractory T-ALL to develop potential targeted therapies. Pediatric T-ALL patient derived T cells were grown under either nonskewingTh0 or Th1-skewing conditions to further process for ChIP-qPCR, RDIP-qPCR and other RT-PCR assays. Endogenous WASp was knocked out using CRISPR-Cas9 and was confirmed using flow cytometry and western blotting. LC-MS/MS was performed to find out proteomic dataset of WASp-interactors generated from Th1-skewed, human primary Th-cells. DNA-damage was assessed by immunofluorescence confocal-imaging and single-cell gel electrophoresis (comet assay). Overexpression of RNaseH1 was also done to restore normal Th1-transcription in WASp-deficient Th1-skewed cells. We discovered that nuclear-WASp is required for suppressing R-loop production (RNA/DNA-hybrids) at Th1-network genes by ribonucleaseH2 (RNH2) and topoisomerase1. Nuclear-WASp is associated with the factors involved in preventing and dissolving R-loops in Th1 cells. In nuclear- WASp-reduced malignant Th1-cells, R-loops accumulate in vivo and are processed into DNA-breaks by transcription-coupled-nucleotide-excision repair (TC-NER). Several epigenetic modifications were also found to be involved at Th1 gene locus which are responsible for active/repressive marks of particular genes. By demonstrating WASp as a physiologic regulator of programmed versus unprogrammed R-loops, we suggest that the transcriptional role of WASp in vivo extends also to prevent transcription-linked DNA damage during malignancy and through modification of epigenetic dysregulations. Our findings present a provocative possibility of resetting R-loops as a therapeutic intervention to correct both immune deficiency and malignancy in T-cell acute lymphoblastic leukemia patients and a novel role of WASp in the epigenetic regulation of T helper cell differentiation in T-ALL patients, anticipating WASp's requirement for the suppression of T-ALL progression.
2024-05-07 | THE POTENTIAL OF HUMAN PLASMA AND HUMAN BLOOD PRODUCTS FOR IMMUNE PROTECTION
Intravenous Immunoglobulin (IVIg) were used for the first time at the late seventies for treatment of patient with primary and secondary immunodeficiencies. Тhe first observations opened a wide field for basic and clinical research leading to a rapidly expanding use of IVIg for the treatment of patients with multiple diseases. The immunoglobulin preparations contain large amount of intact form of IgG molecules with comparable values of subclasses as in native plasma. Тhose properties account for the normal half-life of injected immunoglobulin of three weeks, and its ability to react normal with the complement components and with the specific Fcγ-receptors on the surface of phagocytes and lymphocytes. IVIg is produced from plasma pules from several thousand donors, which leads to wide spectre of variable regions of IgG molecules in the product. Some of the antibodies in the product can recognize bacterial, virus and fungal antigens are essential in replacement therapy in patients with antibody deficiency. А good understanding of the molecular and cellular basis of the immunoregulatory actions of intravenous immunoglobulin preparations is important for optimizing their use in inflammatory diseases for conducting new clinical observations.
cell therapies
2026-07-03 | Atypical Wiskott-Aldrich syndrome presenting with normal platelet volume and end-stage renal disease: from misdiagnosis as ITP to combined transplantation.
We report a 30-year-old male with a novel WAS mutation (c.252C > A, p.F84L) who was misdiagnosed with immune thrombocytopenia (ITP) for years. Despite persistent thrombocytopenia, his mean platelet volume remained normal, an atypical feature of Wiskott-Aldrich syndrome (WAS). His course was complicated by stage-5 chronic kidney disease, renal anemia, IgA nephropathy, and recurrent infections. Laboratory tests consistently showed low lymphocyte counts and reduced WAS protein (WASp) levels. After confirming WAS, the original plan of kidney transplantation alone was changed to combined hematopoietic stem cell and kidney transplantation to restore immunity and reduce graft failure risk. This case highlights that WAS can present with normal platelet volume; thus, WAS should be considered in patients with unexplained chronic kidney disease, recurrent infections, and poor ITP therapy response, even without typical microthrombocytopenia.
2025-04-10 | How I treat Wiskott-Aldrich syndrome.
Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder, characterized by thrombocytopenia, eczema, recurrent infections, autoimmunity, and malignancy. Here, we discuss current conservative and definitive approaches to treating WAS, based on recently published evidence. Disease severity in WAS is highly variable. Recent studies confirm that the probability of disease progression depends on the type of genetic variant, supporting early diagnosis and tailored treatment strategies. Milder cases, historically termed X-linked thrombocytopenia (XLT), received supportive care, whereas severe cases were referred for standard allogeneic hematopoietic cell transplantation (HCT) or gene therapy (GT) in clinical trials. Advances in HCT and GT, together with recent knowledge that even patients with XLT are at risk for severe immune complications, suggest that most young patients with WAS should be offered a potentially curative approach at diagnosis. Older patients with a small subset of milder variants may be treated conservatively unless they develop life-threatening autoimmune or malignant complications; regular monitoring and proactive management are critical to preventing irreversible complications. We recommend discontinuing the term XLT as it implies a mild and uncomplicated disease, which is not the norm, and instead tailor treatment for all patients with WAS to their individual genetic profile, disease severity, and clinical course.
2024-10-26 | Pathophysiology of Congenital High Production of IgE and Its Consequences: A Narrative Review Uncovering a Neglected Setting of Disorders.
Elevated serum IgE levels serve as a critical marker for uncovering hidden immunological disorders, particularly inborn errors of immunity (IEIs), which are often misdiagnosed as common allergic conditions. IgE, while typically associated with allergic diseases, plays a significant role in immune defense, especially against parasitic infections. However, extremely high levels of IgE can indicate more severe conditions, such as Hyper-IgE syndromes (HIES) and disorders with similar features, including Omenn syndrome, Wiskott-Aldrich syndrome, and IPEX syndrome. Novel insights into the genetic mutations responsible for these conditions highlight their impact on immune regulation and the resulting clinical features, including recurrent infections, eczema, and elevated IgE. This narrative review uniquely integrates recent advances in the genetic understanding of IEIs and discusses how these findings impact both diagnosis and treatment. Additionally, emerging therapeutic strategies, such as hematopoietic stem cell transplantation (HSCT) and gene therapies, are explored, underscoring the potential for personalized treatment approaches. Emphasizing the need for precise diagnosis and tailored interventions aims to enhance patient outcomes and improve the quality of care for those with elevated IgE levels and associated immunological disorders.
2024-09-25 | Hematopoietic cell transplantation for inborn errors of immunity: an update on approaches, outcomes and innovations.
Allogeneic hematopoietic cell transplantation (HCT) is a curative option for many for inborn errors of immunity (IEI). This review highlights recent progress in the field of HCT for IEI. Alternative donor transplantation continues to expand donor options for patients with IEI. Reduced intensity and reduced toxicity conditioning approaches are being investigated and optimized. Immunomodulatory bridging therapies are yielding impressive progress in outcomes for primary immune regulatory disorders (PIRD) but require further study in prospective trials. Single-institution, multicenter and consortium studies have improved our understanding of factors that affect overall outcomes in IEI and outcomes in Wiskott-Aldrich syndrome (WAS), chronic granulomatous disease (CGD) and PIRD in particular. Data show that second HCT offers a viable chance of cure to some IEI patients. Late effects in IEI HCT survivors are being better characterized. Preclinical studies of chemo(radiation)-free HCT strategies hold promise for decreasing HCT toxicity. Improvements in our understanding of HCT donor choice, conditioning regimen, immunomodulatory bridging therapies, diagnostic and post-HCT surveillance testing and late effects continue to yield advancements in the field of HCT for IEI.
2024-02-01 | Haploidentical bone marrow transplantation in a pediatric patient with Wiskott-Aldrich syndrome. A case report
Wiskott-Aldrich syndrome (WAS) is an X-linked genetic disorder caused by mutations in the gene that encodes the Wiskott-Aldrich syndrome protein (WASp).Here, we report the clinical case of an 18-month-old boy diagnosed with Wiskott-Aldrich syndrome, who did not have an HLA-matched related or unrelated donor and was treated successfully with a hematopoietic stem cell transplant (HSCT) from a haploidentical family donor.Graft-versus-host disease (GvHD) prophylaxis included post-transplant cyclophosphamide (PT-Cy).At day +30, the peripheral blood-nucleated cell chimerism was 100% and the WAS protein had a normal expression.Currently, at month 32 post-transplant, the patient has hematological and immune reconstitution and complete donor chimerism without evidence of GvHD.HSCT with PT-Cy was a feasible and safe option for this patient with WAS, in which an HLA matched donor was not available.
gene therapies
2026-07-25 | Gene therapy approaches for inborn errors of immunity: from bench to bedside.
Inborn errors of immunity (IEI) are rare genetic defects that disrupt immune function, often resulting in life-threatening infections, malignancies, and immune dysregulation. Allogeneic hematopoietic stem cell transplantation (HSCT), a curative option for some diagnoses, is limited by donor availability and the risks of graft-versus-host disease. This review explores the 30-year evolution of autologous gene therapy as a vital alternative to allogeneic HSCT for IEIs. Literature search using PubMed for gene therapy for IEI in the last 20 years. We trace the transition from early gamma-retroviral gene addition, which successfully restored immunity in severe combined immunodeficiency (SCID) but carried high risks of insertional mutagenesis and leukemogenesis, to the adoption of safer self-inactivating lentiviral vectors. The field is rapidly advancing beyond viral gene addition toward highly precise gene‑editing technologies, including CRISPR/Cas9 and base/prime editing, which offer targeted correction with minimized genotoxicity. Recent milestones in diseases such as Wiskott -Aldrich syndrome (WAS) and chronic granulomatous disease (CGD) highlight enormous scientific success, yet significant barriers to accessibility, manufacturing, and affordability remain. Overcoming this requires innovative regulatory frameworks and collaborative funding models. Streamlining development and ensuring equitable access are essential next steps to establishing gene therapy as a safe alternative.
2026-07-06 | The spectrum of bleeding in Wiskott-Aldrich syndrome: a systematic review and meta-analysis of incidence and mortality
Background Bleeding is the predominant clinical manifestation and one of the leading causes of death of Wiskott-Aldrich syndrome (WAS). However, significant discrepancies in reported bleeding phenotypes persist. Objective This systematic review and meta-analysis aim to provide a comprehensive characterization of the bleeding phenotype and elucidate the resultant mortality burden among patients with WAS. Methods Observational studies reporting either the cumulative incidence of bleeding manifestations or the occurrence of fatal hemorrhagic events in patients with WAS were included. The Joanna Briggs Institute critical appraisal tool was used to assess the risk of bias. A generalized linear mixed model with a binomial-normal distribution was employed for the meta-analysis. Subgroup analyses, stratified by clinical stage at data collection, and meta-regression analyses were conducted to explore heterogeneity. Results A total of 40 studies involving 1865 patients were identified. The pooled cumulative incidences of overall and site-specific bleeding (excluding gastrointestinal bleeding), increased significantly from disease onset to diagnosis and through to the end of follow-up. At the end of follow-up, the pooled cumulative incidence of multisystem bleeding and severe bleeding was 57% (95% CI 41-72) and 19% (95% CI 12-28), respectively. Both sample size and proportion of patients with a WAS score of 5 were associated with cumulative incidence of severe bleeding at the end of follow-up ( p = 0.0042 and 0.0423, respectively). The cause-specific mortality rate from hemorrhage was 9.3% (95% CI: 6.1-13.8; I 2 = 0%) in non-curatively treated patients and 1.0% (95% CI: 0.4-2.4; I 2 = 0%) in curatively treated patients. Curative treatment was associated with a significantly lower risk of fatal hemorrhage compared to non-curative treatment (RR = 0.07, 95% CI 0.01-0.49). The proportional mortality ratio due to hemorrhage was 30% (95% CI 22-39) in non-curatively treated patients. Fatal hemorrhages were highly skewed toward early childhood (median age-at-death: 22 months), with intracranial hemorrhage being the predominant cause of death (76.1%). Conclusions Bleeding complications are nearly universal and progressive in patients with WAS. Given that most fatal hemorrhages occur in early childhood and curative treatment significantly mitigates this risk, prompt implementation of such therapy is imperative. Systematic review registration https://www.crd.york.ac.uk/prospero/ , identifier CRD420261277891.
2026-03-11 | FDA must regulate stem cell therapies to mitigate risks to patients and the public
In December 2025, the US Food and Drug Administration's (FDA's) Center for Biologics Evaluation and Review (CBER) approved a gene-based stem cell therapy for Wiskott-Aldrich syndrome, a rare and life-threatening genetic disease.This decision was appropriately based on data from two clinical studies that demonstrated a clinical benefit.Unfortunately, this standard of evidence, and FDA approval itself, are not the norm for many stem cell therapies.Instead, hundreds, if not thousands, of clinics have made unproven and unapproved stem cell treatments widely available to treat everything from common sports injuries to neurological diseases.Officials from the FDA and other federal agencies have tried to stop this potentially dangerous trade.As part of those efforts, the FDA filed two lawsuits in 2018 against clinics involved in the online promotion of unapproved stem cell therapies.After years of court filings and appeals, the agency won an important court case in late 2024 that confirmed the FDA's power to regulate unproven stem cell therapies.In October 2025, the US Supreme Court declined to reconsider the decision, meaning that after seven years, the FDA had confirmed its regulatory authority over a burgeoning online industry.That's good news for proponents of evidence-based medicine.But for how long will this position hold?This may depend in significant part on the current leadership at the Department of Health and Human Services (HHS), which sits above the FDA.Thus far, the signs are not good.Since Congress' February 2025 confirmation of Robert F. Kennedy, Jr. (RFK Jr.) as Secretary of HHS, changes in the FDA's senior officials and policy priorities suggest that the FDA may back away from exercising the authority to regulate this important field, despite its seven-year battle to do so.Here, we highlight the changes that the current Administration might consider for FDA
2025-12-11 | EMA – First gene therapy to treat rare disease Wiskott-Aldrich syndrome
EMA has recommended granting a marketing authorisation in the European Union (EU) for Waskyra (etuvetidigene autotemcel) to treat people aged 6 months and older with Wiskott-Aldrich syndrome (WAS) who have a mutation in the WAS gene. Waskyra is used to treat patients for whom a haematopoietic stem cell transplantation (HSCT) is appropriate, but for whom no suitable stem cell donor is available. Wiskott-Aldrich syndrome is a rare, inherited disease, seen almost exclusively in males, that affe...
2025-11-03 | National temporal trends and demographic disparities in primary immunodeficiency-related mortality in the United States, 1999–2024
Abstract Background: Primary immunodeficiency disorders (PIDs) comprise hundreds of rare, genetically defined conditions that confer susceptibility to infection, autoimmunity, and early death. Although therapeutic advances and neonatal screening have improved outcomes, contemporary population-level evidence on PID mortality and equity is limited. This study aimed to quantify national trends in PID-related mortality and to characterize disparities by race, sex, and urbanization. Methods: We extracted data from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) Multiple Cause-of-Death (MCD) database, identifying all U.S. deaths from January 1, 1999, through December 31, 2024, where the cause of death had ICD-10 codes D80–D84 listed as MCD. This spectrum encompasses predominantly antibody deficiencies (D80: hereditary or nonfamilial hypogammaglobulinemia, selective IgA/IgG/IgM deficiencies, hyper-IgM syndromes, and related entities), combined immunodeficiencies including classic severe combined immunodeficiency and its genetic variants (D81), syndromic or major-defect-associated immunodeficiencies such as Wiskott-Aldrich, DiGeorge, and hyper-IgE syndromes (D82), common variable immunodeficiency and its sub phenotypes (D83), and other specified or unspecified immunodeficiencies such as LFA-1 or complement defects (D84). Age-adjusted mortality rates (AAMRs) per 1,000,000 population were calculated by direct standardization to the 2000 U.S. population. Joinpoint regression generated annual percent change (APC) and average annual percent change (AAPC) for the overall population and strata defined by sex and race/ethnicity (non-Hispanic Black, non-Hispanic White, Hispanic). Urban–rural residence was examined with the 2013 NCHS Urban–Rural Classification, which CDC WONDER provides only through 2020; therefore, urbanization analyses cover 1999–2020. Mortality data for 2024 are provisional. Results: During the 26-year interval between 1999 and 2024, 27,616 PID-related deaths occurred. The overall AAMR declined from 4.85 in 1999 to 3.15 in 2024, corresponding to an AAPC of –1.33 %. Throughout the study, men retained higher AAMR than women (2024: 3.4 vs 2.9), yet both sexes showed significant declines (AAPC –1.9 % and –1.1 %, respectively). Initially, non-Hispanic Black individuals faced the highest burden, with an AAMR of (11.2) compared to (4.3) among non-Hispanic Whites and 3.8 among Hispanics. Remarkably, Blacks exhibited the steepest sustained improvement (AAPC –4.9%), such that by 2024 their mortality rate had fallen to 3.7, only marginally higher than Whites (3.4) and Hispanics (3.0). The Black-to-White gap narrowed from 2.6-fold to approximately 1.1-fold. From 1999 to 2020, rural residents consistently had higher mortality rates than urban residents; although both groups improved, the decline plateaued after 2015, with an AAPC of -2.45% and -3.36%, respectively. Conclusions: National PID-related mortality has decreased significantly since 1999, mainly due to rapid declines among non-Hispanic Black Americans, nearly eliminating long-standing racial disparities. Ongoing higher mortality rates among males and rural communities, along with a recent slowdown in progress, highlight the need for more access to newborn screening, curative treatments, and specialized care for all populations.
other
2025-11-21 | Dupilumab for atopic manifestations in pediatric patients with inborn errors of immunity: efficacy and safety in a genetically diverse cohort
Background Inborn Errors of Immunity (IEI) are monogenic disorders that predispose patients to infections, autoimmunity, atopy, and malignancies. Severe Th2-driven atopic dermatitis and asthma are common in several IEIs, including DOCK8 deficiency, STAT3 loss-of-function, and Wiskott–Aldrich syndrome, often refractory to conventional therapies. Dupilumab, a monoclonal antibody targeting IL-4Rα, has shown promise in managing recalcitrant atopic dermatitis and asthma, but data in immunocompromised pediatric populations remain limited. Methods We conducted a single-center, retrospective observational cohort study with prospective follow-up of ten pediatric patients with genetically confirmed IEI and atopic manifestations. Patients received subcutaneous dupilumab (300 mg every 4 weeks for atopic dermatitis; every 2 weeks for severe asthma). Outcomes were assessed using the Eczema Area and Severity Index (EASI), Dermatology Life Quality Index (DLQI), Childhood Asthma Control Test (C-ACT), eosinophil counts, and infection frequency across four time points (baseline, 6 months, 12 months, >18 months). Results The cohort included ten patients (6 males, 4 females) with mutations in DOCK8 (n=5), CARD11 (n=2), STAT3 LOF (n=1), ADA (n=1), and PEPD (n=1). Of ten patients, nine received dupilumab for atopic dermatitis. Baseline EASI and DLQI scores were 34.33 and 25.0, respectively. Following dupilumab therapy, mean EASI decreased to 2.67 (p<0.001) and DLQI improved to 2.67 (p<0.001), with sustained response observed over 18 months. Peripheral eosinophil counts declined from 2.0×10 9 /L to 0.45×10 9 /L (p<0.001). One patient with severe asthma achieved C-ACT improvement from 10 to 26 with no subsequent exacerbations. Treatment was well-tolerated, with only mild conjunctivitis or transient hypereosinophilia reported. Notably, skin infections resolved, and no systemic or opportunistic infections were observed. Conclusion Dupilumab is a safe and highly effective therapeutic option for pediatric patients with IEI-associated atopic manifestations, improving clinical outcomes, quality of life, and infection profile while preserving immune function. These findings support broader application of dupilumab in patients with IEI and warrant further investigation in larger, multicenter studies.
2025-11-03 | The clinical observation of treating autoimmune cytopenias after allogeneic hematopoietic stem cell transplantation in children by immunoinduction therapy
Abstract This retrospective study explored safety and efficacy of immunoinduction methods such as Immunosuppressants are reduced and discontinued, with or without PD1 inhibitors, or donor lymphocyte reinfusion (DLI) in the treatment of autoimmune cytopenias (AIC) after allogeneic hematopoietic stem cell transplantation. The clinical data of 20 children admitted to Beijing JingDu Children's Hospital from January 2019 to May 2025 with AIHA (10 cases), ITP (7 cases), and Evans syndrome (3 cases) after allogeneic hematopoietic stem cell transplantation were retrospectively analyzed (5-AA; 4-chronic granulomatous disease; 3-HLH; 2-Wiskott-Aldrich syndrome; 1- Congenital neutropenia; 1-ALL; 1-pyruvate kinase deficiency anemia; 1-Thalassemia; 1-Mucopolysaccharidosis type I; 1-Mucopolysaccharidosis type Ⅱ). Among the 20 cases, 7 cases had mixed chimerism and 13 cases had complete chimerism at the onset of AICs. In all cases, corticosteroids were treated with or without IVIG and rituximab for 1 to 5 weeks, and then Immunosuppressants such as cyclosporine or tacrolimus etc, are reduced and discontinued, combined with or without PD1 inhibitors and DLI were used to treat AICs. The median age of AICs in 20 children was 4 (range:1.25-17) years; median time to development of AICs: 9 (range:4-68) months after transplantation; the median number of recurrent episodes of AICs was 2 (1-5) times. ATG was used in the conditioning regimen of 20 children. Among the 20 children, 5 children cured after stopping immunosuppressants, and 15 children were cured after stopping immunosuppressants combined with PD1 inhibitors or DLI, the average duration of treatment is 2 (0.5-6) months. Among the 20 children, 11 children had grade I~II skin or liver rejection, which were controlled after topical medication or short-term low-dose immunosuppressant therapy. At a median follow-up of 20(2-62) months after discontinuation of treatment, none of the children had recurrence. The immunoinduction therapy of AICs after allogeneic hematopoietic stem cell transplantation is safe and effective.
2025-10-20 | Atopic dermatitis in inborn errors of immunity: at the interface of immunodeficiency and immune dysregulation.
Inborn errors of immunity (IEI) encompass a broad spectrum of immunodeficiency disorders characterized by variability in genetic background, individual immunophenotype, and clinical manifestations with organ-specific immunopathology and immune dysregulation in the form of atopy, autoimmunity, polyclonal lymphoproliferation, and malignancy. With the ever-expanding insight in the pathophysiology of IEI, atopy may be perceived as an integral part and even a hallmark of IEI diseases. This review is aimed at gathering, delineating, and summarizing the immunogenetic underpinnings of IEI diseases accompanied by atopic dermatitis. Particular emphasis is laid on syndromes connected with atopy, such as hyper-IgE syndromes, Omenn syndrome, immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, Netherton syndrome, Wiskott-Aldrich syndrome, and atypical complete DiGeorge syndrome. Therefore, atopic dermatitis proved not to be a sole disease, but rather a warning sign of multiple pediatric monogenic immunodeficiency disorders. Surpassing from the era of clinical and immunological diagnosis to the era of immunogenetics and the integrated "omics" approach highlighted the complex and heterogeneous immunopathology of atopic dermatitis. It also paved the way for patient-tailored immunotherapies with monoclonal antibodies and small molecules targeted at suppressing atopic inflammatory processes and improving disease-associated outcomes.
2025-02-25 | Dupilumab successfully controlled eczema in Wiskott-Aldrich Syndrome over 52 weeks.
Wiskott-Aldrich syndrome (WAS) is a rare genetic disorder characterized by immunodeficiency, thrombocytopenia, and eczema. The Management of eczema remains still a major clinical challenge. We present a rare case of eczema associated with WAS in an 8-year-old boy whose lesions significantly improve after a 4-week treatment of dupilumab, a interleukin(IL)-4α receptor monoclonal antibody. Although eczema relapsed after stopping dupilumab, and alleviated after dupilumab was resumed. Finally, the Eczema Area and Severity Index (EASI) score decreased to less than 7 after the patient receive dupilumab 300 mg every 4 weeks over 52 weeks. This case suggests that dupilumab is a promising therapy alternative for patient with eczema in WAS.
2024-07-26 | Interleukin-1 blockade in patients with Wiskott-Aldrich syndrome: a retrospective multinational case series.
Up to 70% of patients with Wiskott-Aldrich syndrome (WAS) develop autoimmune and inflammatory manifestations. Dysregulation of interleukin 1 (IL-1) may be involved in their pathogenesis, yet there is little evidence on treatment with anti-IL-1 agents in these patients. We conducted a multicenter retrospective analysis of 9 patients with WAS treated with anti-IL-1 agents (anakinra or canakinumab). All patients had prominent inflammatory manifestations, including systemic, cutaneous, articular, and intestinal symptoms; 3 patients presented with a severe systemic inflammatory syndrome since the first months of life. Corticosteroid therapy was associated with partial or no response, whereas treatment with anakinra or canakinumab resulted in prompt, often dramatic, responses in all patients, allowing bridging to gene therapy (4 patients) or hematopoietic stem cell transplantation (HSCT; 5 patients). Treatment was overall well tolerated. Low donor myeloid chimerism developed in 4 patients after HSCT and was associated with the appearance or the recurrence of inflammatory manifestations. A second HSCT was performed in 2 patients, achieving full-donor chimerism and resolution of inflammatory manifestation, whereas the other 2 patients were treated with prolonged therapy with anti-IL-1 agents. Our experience demonstrates that some inflammatory manifestations of WAS are dependent on IL-1 and respond well to its pharmacologic blockade.
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Drug Discovery Landscape
8 orphan drug designations for Wiskott-Aldrich syndrome, including 2 approved therapies.
8 orphan drug designations for Wiskott-Aldrich syndrome, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
autologous CD34+ cells edited using specific CRISPR/Cas9 system and transduced with an adeno-associated vector containing a codon-optimized version of WAS gene (coWAS) | gene editing enzymes | FDA | — | Danaus Pharmaceutical S.L. |
Autologous CD34+ cells edited with a CRISPR/Cas9 system and transduced with an adeno-associated vector containing a codon-optimized version of WAS gene | cell therapies | EMA | — | Danaus Pharmaceuticals S.L. |
autologous cluster of differentiation 34 positive (CD34+) hematopoietic stem/progenitor cells transduced with the LVMWAS lentiviral vector encoding the human Wiskott-Aldrich Syndrome protein | gene therapies | FDA | — | Seattle Children’s Therapeutics |
Autologous CD34+ hematopoietic stem and progenitor cells modified ex vivo with a lentiviral vector that restores endogenously regulated expression of WASp | cell therapies | FDA | — | ImmunoVec |
Autologous CD34+ cells transduced with a lentiviral vector containing the human Wiskott-Aldrich syndrome gene | cell therapies | EMA | Généthon | |
Autologous CD34+ cells transfected with lentiviral vector containing the Wiskott-Aldrich syndrome protein gene [Waskyra] | gene therapies | EMA | Approved | Fondazione Telethon Ets |
etuvetidigene autotemcel [Waskyra] | gene therapies | FDA | Approved | Fondazione Telethon ETS |
Etuvetidigene autotemcel | gene therapies | EMA | Genethon |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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