Mallhi Kanwaldeep K, Petrovic Aleksandra, Ochs Hans D
Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
J Blood Med. 2021 Jun 11;12:435-447. doi: 10.2147/JBM.S232650. eCollection 2021.
The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder caused by mutations in the 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.
威斯科特-奥尔德里奇综合征（WAS）是一种X连锁疾病，由该基因的突变引起，导致先天性血小板减少、湿疹、反复感染以及自身免疫性疾病和恶性肿瘤的发病率增加。如果没有治愈性疗法，受影响患者的预期寿命会缩短，生活质量会下降。由于WAS蛋白（WASP）仅在造血干细胞衍生的谱系中组成性表达，造血干细胞移植（HSCT）和基因治疗（GT）非常适合纠正血液学和免疫学缺陷。高分辨率HLA分型的进展、允许使用单倍体相合供体的预防移植物抗宿主病（GvHD）的新技术以及引入具有清髓特征的减低强度预处理方案，使总生存率（OS）提高到了90%以上。WAS基因治疗的发展为载体选择以及各种病毒载体随机整合到基因组中提供了基础知识，同时也存在诱导白血病发生的可能性。经过反复试验，携带WAS基因的失活慢病毒载体在临床试验中得到了成功评估，除血小板缺陷解决不充分外，证明了该疾病可治愈。因此，经过50年的临床评估、基因探索和广泛的临床试验，一种致命综合征已变成一种可治愈的疾病。
