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.

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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.

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