Preclinical ex vivo IL2RG gene therapy using autologous hematopoietic stem cells as an effective and safe treatment for X-linked severe combined immunodeficiency disease  

作　　者：Mingfeng Hu Qiling Xu Fang Zhang Karen F.Buckland Yelei Gao Weixia Du Yuan Ding Lina Zhou Xiulian Sun Lijia Ma Zhiyong Zhang Xuemei Tang Xiaodong Zhao Adrian J.Thrasher Yunfei An 

机构地区：[1]Department of Pediatric Research Institute,Ministry of Education Key Laboratory of Child Development and Disorders,National Clinical Research Center for Child Health and Disorders(Chongqing),China International Science and Technology Cooperation Base of Child Development and Critical Disorders,Children’s Hospital of Chongqing Medical University,Chongqing 400014,China [2]Chongqing Key Laboratory of Child Infection and Immunity,Children’s Hospital of Chongqing Medical University,Chongqing 400014,China [3]Department of Rheumatology and Immunology,Children’s Hospital of Chongqing Medical University,Chongqing 400014,China [4]UCL Great Ormond Street Institute of Child Health,London WC1N 1EH,UK [5]Ubrigene(Beijing)Biosciences Co.Ltd,Beijing 100080,China [6]Genome Editing,Westlake Laboratory of Life Sciences and Biomedicine,Hangzhou,Zhejiang 310024,China

出　　处：《Genes & Diseases》2025年第3期397-410,共14页基因与疾病(英文)

基　　金：supported by the National Natural Science Foundation of China(No.82070135);the National Key R&D Program of China(No.2021YFC2700804);the CQMU Program for Youth Innovation in Future Medicine(China)(No.W0100).

摘　　要：X-linked severe combined immunodeficiency disease(X-SCID)is a rare inheriteddisease caused by mutations in the interleukin 2 receptor subunit gamma gene(IL2RG),whichencodes the common g chain protein,a subunit of the receptor for lymphocytes.X-SCID ischaracterized by profound defects in T-cell,B-cell,and natural killer cell function.Here,we report a Chinese cohort of nine X-SCID patients with six novel IL2RG mutations.Amongthose,the two adolescent patients with an atypical immunotype were confirmed by furtheranalyzing IL-2-JAK-STAT5 signaling,T cell proliferation,and T cell receptor excision circles(Trecs).Interestingly,Bacillus Calmette-Guerin(BCG)disease occurred commonly in thiscohort.Although allogeneic hematopoietic stem-cell transplantation is curative for the disease,it is not available to all patients due to the lack of suitable matched donors.Autologousgene therapy using a self-inactivating lentiviral vector(SIN-LV)technology has provided analternative therapy for such mono-genetic diseases.Here,we performed the pre-clinicalstudies to assess our SIN-LV carrying IL2RG on human ED7R cells deficient in IL2RG andCD34^(+)stem cells derived from the bone marrow of a healthy donor and a patient with X-SCID.This work is done complied with the established“Good Manufacturing Practice”(GMP)used inthe clinical trials.In addition,a safety study is performed using the transduced CD34^(+)cells implanted into the axilla of nude mice in vivo.Overall,our studies have demonstrated the efficiency and safety of SIN-IL2RG-LV,which paves the way for conducting X-SCID gene therapyclinical trials in China in the near future.

关 键 词：Atypicaldiverse phenotype Gene therapy IL2RG Self-inactivating lentiviral vector X-linked severe combined immunodeficiency disease 

分 类 号：R725.9[医药卫生—儿科]