Gene therapy may be helpful for Wiskott-Aldrich Syndrome

1. In this study of seven individuals with Wiskott-Aldrich Syndrome (WAS), gene therapy improved eczema, susceptibility to infection, autoimmunity, and T cell function.

2. While the presence of WAS protein expressing B cells may indicate an improvement in humoral immune function, the timeframe of the study was too short to fully assess functional outcomes in humoral immunity.

Evidence Rating Level: 3 (Average)   

Study Rundown: Wiskott-Aldrich Syndrome (WAS) is an X-linked primary immunodeficiency that results in bleeding, eczema, susceptibility to infection, autoimmunity, and an increased risk of lymphoid malignancy. While stem cell transplantation can be curative, it can be accompanied by many complications. This study reported on seven patients from England and France with WAS who were treated with gene therapy with a self-inactivating lentivirus vector between December 2010 and January 2014. Autologous hematopoietic stem cells were treated with the lentivirus gene therapy and reinfused after myeloablative conditioning.

Six of seven patients were evaluable for 9 months and those six were all alive and showed clinical improvement in December 2014. Eczema, susceptibility to infections, and autoimmune conditions improved in all cases. There was also evidence of correction of T cell function. The study was too short to assess the functional outcomes in humoral immunity, but the presence of WAS protein expressing B cells may indicate improvement. This study is limited by its small sample size and limited time course. Thus, while this study does suggest that gene therapy may be helpful in individuals with WAS, a larger trial is needed to more completely understand the utility of this therapeutic modality.

Click to read the study, published today in JAMA

Click to read an accompanying editorial, published today in JAMA

Relevant Reading: Gene therapy for Wiskott-Aldrich syndrome–long-term efficacy and genotoxicity.

In-Depth [prospective cohort]: This study included seven individuals aged 0.8-15.5 years (median 7 years) with WAS who were given a single infusion with lentivirus gene therapy treated CD-34+ from bone marrow (4 cases) or mobilized peripheral blood (3 cases). One month after treatment, vector positive cells were detectable in blood, with 0.35 to 1.20 copies noted in CD3+ T cells, 0.1 to 1.34 in CD19+ B cells, and 0.04 to 0.7 in sorted natural killer CD56+ cells. Six of the seven patients were evaluable 9 months after the intervention and those six individuals were alive and clinically improved December 2014. One patient died of septic shock 7 months after gene therapy after contracting multiple drug resistant opportunistic herpes virus infections. Eczema, susceptibility to infection, and autoimmunity resolved in all study participants. Platelet count and volume improved in 3 individuals but remained low in all participants (mean patient platelet volume ranged 8.1-9.3 fL compared to healthy control platelet volume range of 7.5 to 10.1 fL). T cell function improved with values reaching that of normal absolute T cell counts in most patients. While the presence of WAS protein expressing B cells may signify improved humoral immunity, B cell function was not fully evaluated in 4 of the 6 patients who were still receiving immunoglobulin therapy.

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