Until recently, hematopoietic stem cell transplantation was the only curative option for Wiskott-Aldrich syndrome (WAS). The first attempts at gene therapy for WAS using a ϒ-retroviral vector improved immunological parameters substantially but were complicated by acute leukemia as a result of insertional mutagenesis in a high proportion of patients. More recently, treatment of children with a state-of-the-art self-inactivating lentiviral vector (LV-w1.6 WASp) has resulted in significant clinical benefit without inducing selection of clones harboring integrations near oncogenes. Here, we describe a case of a presplenectomized 30-year-old patient with severe WAS manifesting as cutaneous vasculitis, inflammatory arthropathy, intermittent polyclonal lymphoproliferation, and significant chronic kidney disease and requiring long-term immunosuppressive treatment. Following reduced-intensity conditioning, there was rapid engraftment and expansion of a polyclonal pool of transgene-positive functional T cells and sustained gene marking in myeloid and B-cell lineages up to 20 months of observation. The patient was able to discontinue immunosuppression and exogenous immunoglobulin support, with improvement in vasculitic disease and proinflammatory markers. Autologous gene therapy using a lentiviral vector is a viable strategy for adult WAS patients with severe chronic disease complications and for whom an allogeneic procedure could present an unacceptable risk. This trial was registered at www.clinicaltrials.gov as #NCT01347242.

直到最近，造血干细胞移植还是Wiskott-Aldrich综合征（WAS）的唯一治疗选择。使用β-逆转录病毒载体进行WAS基因治疗的首次尝试显着改善了免疫学参数，但由于插入诱变而使高比例的患者因急性白血病而变得复杂。最近，用最先进的自灭活慢病毒载体（LV-w1.6 WASp）治疗儿童已获得显着的临床益处，而没有诱导选择在癌基因附近具有整合的克隆。在这里，我们描述了一例经脾切除术的30岁患者，患有严重的WAS，表现为皮肤血管炎，炎性关节炎，间歇性多克隆淋巴增生，以及严重的慢性肾脏疾病，需要长期的免疫抑制治疗。强度降低后，转基因阳性功能性T细胞的多克隆库迅速移入并扩增，并在长达20个月的观察中持续存在于髓样和B细胞谱系中的基因标记。该患者能够终止免疫抑制和外源性免疫球蛋白支持，并改善了血管疾病和促炎性标志物。使用慢病毒载体的自体基因疗法对于患有严重慢性疾病并发症且同种异体手术可能带来不可接受风险的成年WAS患者是一种可行的策略。该审判已在处注册 在长达20个月的观察中，骨髓和B细胞谱系中转基因阳性功能性T细胞的多克隆库迅速移入并扩增，并持续存在基因标记。该患者能够终止免疫抑制和外源性免疫球蛋白支持，并改善了血管疾病和促炎性标志物。使用慢病毒载体的自体基因疗法对于患有严重慢性疾病并发症且同种异体手术可能带来不可接受风险的成年WAS患者是一种可行的策略。该审判已在处注册 在长达20个月的观察中，骨髓和B细胞谱系中转基因阳性功能性T细胞的多克隆库迅速移入并扩增，并持续存在基因标记。该患者能够终止免疫抑制和外源性免疫球蛋白支持，并改善了血管疾病和促炎性标志物。使用慢病毒载体的自体基因疗法对于患有严重慢性疾病并发症且同种异体手术可能带来不可接受风险的成年WAS患者是一种可行的策略。该审判已在处注册 改善血管疾病和促炎指标。使用慢病毒载体的自体基因疗法对于患有严重慢性疾病并发症且同种异体手术可能带来不可接受风险的成年WAS患者是一种可行的策略。该审判已在处注册 改善血管疾病和促炎指标。使用慢病毒载体的自体基因疗法对于患有严重慢性疾病并发症且同种异体手术可能带来不可接受风险的成年WAS患者是一种可行的策略。该审判已在处注册www.clinicaltrials.gov为＃NCT01347242。