Hematopoietic Cell Transplantation in Wiskott-Aldrich Syndrome

Wiskott-Aldrich syndrome is a rare X-linked immunodeficiency characterised by microthrombocytopaenia, eczema and recurrent infections, caused by mutations in the gene encoding Wiskott–Aldrich syndrome protein (WASp). Haematopoietic cell transplantation, encompassing both allogeneic stem cell grafts and emerging autologous gene‐corrected approaches, offers the only definitive cure. In allogeneic settings, selection of a matched sibling or unrelated donor and the intensity of the preparative regimen have a direct impact on engraftment, immune reconstitution and long-term survival. Graft-versus-host disease and mixed chimerism remain major hurdles, particularly where reduced‐intensity conditioning is used to minimise toxicity. In parallel, lentiviral vector‐mediated gene therapy of autologous haematopoietic stem/progenitor cells has entered clinical trials, demonstrating stable multi-lineage engraftment without the need for a matched donor. Collectively, these strategies aim to reconstitute functional immune and platelet compartments, reduce autoimmunity and prevent lymphoid malignancies, thereby transforming the clinical outlook for affected children worldwide.

Research from Nature Portfolio

Recent studies have demonstrated long-term safety and efficacy of lentiviral gene therapy in patients lacking an HLA-matched donor. Following infusion of autologous gene-corrected haematopoietic stem/progenitor cells, stable engraftment was observed over a median follow-up of eight years, with resolution of severe infections, eczema and autoimmunity despite only partial platelet correction. No vector-related adverse events were reported, highlighting tolerability over extended periods. Complementary mechanistic work has elucidated how absence of WASp in donor-derived dendritic cells alters the balance of actin regulators, notably enhancing Rac2-driven antigen cross-presentation to CD8+ T cells. Such insights refine our understanding of immune reconstitution dynamics after transplantation and may inform strategies to optimise graft function.

Hematopoietic Cell Transplantation in Wiskott-Aldrich Syndrome publication trend

The graph below shows the total number of articles in hematopoietic cell transplantation in wiskott-aldrich syndrome across all publications each year (not limited to Nature Index journals).

Technical terms

Haematopoietic cell transplantation: Transfer of stem or progenitor cells capable of repopulating the bone marrow and restoring blood and immune cell lineages.

Allogeneic: Use of stem cells donated by another individual, ideally matched at key HLA loci to reduce rejection and graft-versus-host disease.

Autologous: Use of the patient’s own stem cells, often modified ex vivo to correct a genetic defect before reinfusion.

Engraftment: Successful homing, survival and proliferation of transplanted cells in the recipient’s bone marrow.

Lentiviral vector: A gene‐delivery tool derived from lentiviruses, used to introduce a functional copy of a gene into patient HSCs for long-term expression.

Conditioning regimen: Pre-transplant treatment, ranging from myeloablative to reduced intensity, designed to create space in the marrow and suppress the immune system for engraftment.

Graft-versus-host disease: Immunological attack by donor-derived immune cells against recipient tissues, a common complication of allogeneic transplantation.

References

1. Long-term safety and efficacy of lentiviral hematopoietic stem/progenitor cell gene therapy for Wiskott–Aldrich syndrome. Nature Medicine (2022).
2. B-cell reconstitution after lentiviral vector–mediated gene therapy in patients with Wiskott-Aldrich syndrome. Journal of Allergy and Clinical Immunology (2015).
3. Deletion of Wiskott–Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells. Nature Communications (2016).
4. Wiskott Aldrich Syndrome: A Multi-Institutional Experience From India. Frontiers in Immunology (2021).