Phase 1 Study of Interleukin-2 in Wiskott-Aldrich Syndrome

描述（由申请人提供）： Wiskott-Aldrich综合征（WAS）是一种罕见的先天性疾病，每50万活产婴儿中就有1例。Wiskott-Aldrich综合征蛋白（WASp）的突变导致免疫细胞的宿主防御能力显著降低。因此，Wiskott-Aldrich综合征患者的预期寿命大大缩短，在年轻时就死于致命的血液恶性肿瘤和疱疹病毒感染。目前Wiskott-Aldrich综合征的治疗选择是次优的。造血干细胞移植（HSCT）的失败率约为30%，仅是Wiskott-Aldrich综合征患者的一个选择。数据表明，移植需要在5岁之前进行，并且只有在合适的匹配供体可用时才能进行。Wiskott-Aldrich综合征的轻度形式确实存在，然而，这些具有9年的中位无事件生存期，通常导致在儿童期后期诊断，通常对于移植来说为时已晚。其他治疗选择，包括抗体替代疗法和预防性抗生素，是有限的，最小的治疗效用。宿主对病毒感染和恶性肿瘤的防御需要自然杀伤（NK）细胞，它可以天生识别并杀死受影响的细胞。在没有肌动蛋白分支蛋白WASp的情况下，自然杀伤细胞不能与靶细胞正确地形成免疫突触，这限制了它们的细胞毒性功能。然而，体外研究表明，白细胞介素（IL）-2可以通过诱导WAVE 2（一种替代肌动蛋白分支蛋白）来恢复WASP缺陷型自然杀伤细胞的功能。最近开展了一项1期临床试验，以确定白细胞介素-2在Wiskott-Aldrich综合征中的安全性和耐受性。资助申请将允许支持进行和完成这项试验，评估自然杀伤细胞功能的恢复和细胞骨架动力学作为次要终点。 本研究的具体目的是：1）使用预期增加自然杀伤细胞功能的剂量确定白介素-2在Wiskott-Aldrich综合征中是否安全耐受，2）确定白介素-2给药是否恢复Wiskott-Aldrich综合征患者的自然杀伤细胞功能。

DESCRIPTION (provided by applicant): Wiskott-Aldrich syndrome (WAS) is a rare congenital disease affecting 1 in 500,000 live births. Mutations in the Wiskott-Aldrich Syndrome protein (WASp) result in immune cells with significantly reduced capacity for host defense. As a result, Wiskott-Aldrich Syndrome patients have substantially shortened life expectancies, succumbing at young ages to fatal hematologic malignancies and herpes virus infections. Current therapeutic options for Wiskott-Aldrich Syndrome are suboptimal. Hematopoietic stem cell transplantation (HSCT) carries a failure rate of approximately 30% and is only an option for a subset of Wiskott-Aldrich Syndrome patients. Data suggest that transplantation needs to be performed prior to age 5 and only when a suitably matched donor is available. Milder forms of Wiskott-Aldrich Syndrome do exist, however, these have a median event-free survival of 9 years, typically resulting in diagnosis later in childhood, often too late for transplantation. Other therapeutic options, including antibody replacement therapy and prophylactic antibiotics, are limited and of minimal therapeutic utility. Host defense against viral infection and malignancy requires natural killer (NK) cells, which can innately recognize and kill affected cells. In the absence of the actin branching protein WASp, natural killer cells do not properly form immunologic synapses with target cells, which limits their cytotoxic function. In vitro studies, however, have shown that interleukin (IL)-2 can restore function to WASp-deficient natural killer cells by inducing WAVE2, an alternative actin-branching protein. A Phase 1 clinical trial was recently opened to determine the safety and tolerability of Interleukin-2 in Wiskott-Aldrich Syndrome. The grant application will allow support for conducting and completing this trial, evaluating the restoration of natural killer cell function an cytoskeletal dynamics as secondary endpoints. The Specific Aims of the study are: 1) To determine if Interleukin-2 is safely tolerated in Wiskott-Aldrich Syndrome using doses expected to increase natural killer cell function and 2) To determine if Interleukin-2 administration restors natural killer cell function in Wiskott-Aldrich Syndrome patients.