Hematopoietic Stem Cell Therapy for Wiskott–Aldrich Syndrome: Improved Outcome and Quality of Life

Abstract

The Wiskott–Aldrich syndrome (WAS) is an X-linked disorder caused by mutations in the WAS gene resulting in congenital thrombocytopenia, eczema, recurrent infections and an increased incidence of autoimmune diseases and malignancies. Without curative therapies, affected patients have diminished life expectancy and reduced quality of life. Since WAS protein (WASP) is constitutively expressed only in hematopoietic stem cell-derived lineages, hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) are well suited to correct the hematologic and immunologic defects. Advances in high-resolution HLA typing, new techniques to prevent GvHD allowing the use of haploidentical donors, and the introduction of reduced intensity conditioning regimens with myeloablative features have increased overall survival (OS) to over 90%. The development of GT for WAS has provided basic knowledge into vector selection and random integration of various viral vectors into the genome, with the possibility of inducing leukemogenesis. After trials and errors, inactivating lentiviral vectors carrying the WAS gene were successfully evaluated in clinical trials, demonstrating cure of the disease except for insufficient resolution of the platelet defect. Thus, 50 years of clinical evaluation, genetic exploration and extensive clinical trials, a lethal syndrome has turned into a curable disorder.

Autoimmunity in Wiskott–Aldrich Syndrome: Updated Perspectives

“… 30 , 37 HSCT with TCRαβ/CD19 depletion or posttransplant cyclophosphamide therapy for haploidentical donors has shown promising results and new opportunities for successful curative therapy in WAS/XLT. 127 …”

“…Gene therapy was attempted with a gibbon ape leukemia virus γ-retroviral vector in 2006. 77 , 127 Though successful engraftment was reported, it was limited by development of leukemia due to insertional leukemogenesis. Subsequently, therapy with a lentiviral vector was attempted in 31 patients with WAS.…”

“…Resolution of autoimmune manifestations was also demonstrated with gene therapy; however, the rate of de novo autoimmunity posttransplant was comparable with HSCT. 127 …”

“…30,37 HSCT with TCRαβ/CD19 depletion or posttransplant cyclophosphamide therapy for haploidentical donors has shown promising results and new opportunities for successful curative therapy in WAS/XLT. 127 Gene therapy is an evolving and promising alternative approach when a transplant is not feasible due to unavailability of matched donors. Gene therapy was attempted with a gibbon ape leukemia virus γ-retroviral vector in 2006.…”

“…Resolution of autoimmune manifestations was also demonstrated with gene therapy; however, the rate of de novo autoimmunity posttransplant was comparable with HSCT. 127 Chemoprophylaxis with antimicrobials and monthly VIg are often used for prevention of infections. Management is usually individualized based on disease severity.…”