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
612 drug discovery papers about Wiskott-Aldrich syndrome, with 4 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
612 drug discovery papers about Wiskott-Aldrich syndrome, with 4 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
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.
2026-07-03 | 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.
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.
2026-07-25 | 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.
2026-07-03 | 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.
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.
Access all drug discovery papers and probability of success in trials forecasts:
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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 | Regulator | Orphan designation | Approval | 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 | 2026-07-22 | — | 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 | 2024-08-21 | — | 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 | 2024-03-20 | — | CSL Behring |
Autologous CD34+ hematopoietic stem and progenitor cells modified ex vivo with a lentiviral vector that restores endogenously regulated expression of WASp | cell therapies | FDA | 2023-10-18 | — | ImmunoVec |
Autologous CD34+ cells transduced with a lentiviral vector containing the human Wiskott-Aldrich syndrome gene | cell therapies | EMA | 2013-10-07 | — | Généthon |
Autologous CD34+ cells transfected with lentiviral vector containing the Wiskott-Aldrich syndrome protein gene [Waskyra] | gene therapies | EMA | 2012-06-06 | 2026-01-12 | Fondazione Telethon Ets |
etuvetidigene autotemcel [Waskyra] | gene therapies | FDA | 2010-04-30 | 2025-12-09 | Fondazione Telethon ETS |
Etuvetidigene autotemcel | gene therapies | EMA | 2006-01-24 | — | Genethon |
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