血友病是一种由于X染色体上凝血因子基因突变所致的遗传性出血性疾病,目前主要的治疗方法是凝血因子替代疗法。但长期频繁的注射用药往往导致患者依从性差,容易产生抑制性抗体,从而影响治疗效果。虽然现在延长半衰期的新型凝血因子药物、人源化双特异性抗体以及抗组织因子途径抑制剂单克隆抗体等用于疾病治疗,在给药方式和作用持续时间上已有很大进步,但它们仍无法治愈血友病。因此,以疾病根治为重要目标的基因治疗被设计出来,近年来受到了广泛的关注。该文介绍了血友病基因治疗的原理、基因治疗载体的选择、基因治疗预处理方案,总结了现阶段基因治疗临床应用的安全性和有效性;最后讨论基因治疗目前存在的问题以及未来发展方向。

Hemophilia is a genetic bleeding disorder resulting from mutations in coagulation factor genes on the X chromosome．The mainstay of current treatment is coagulation factor replacement therapy．However,frequent and long-term injections often lead to poor patient compliance,easy inhibitor development,and compromised therapeutic efficacy．Despite advancements in delivery methods and prolonged action of novel agents such as extended half-life coagulation factor concentrates,humanized bispecific antibodies,and anti-tissue factor pathway inhibitor monoclonal antibodies,these approaches still fall short of curing hemophilia．Consequently,gene therapy,aiming for disease eradication,has garnered significant attention in recent years．This review delves into the principles of gene therapy,the selection of gene therapy vectors,and gene therapy preconditioning regimens．It summarizes the safety and efficacy of gene therapy in current clinical applications and discusses challenges and future directions in this field．

目的 对儿童重症肺炎支气管肺泡灌洗液(BALF)进行病原学分析及疾病预后的分析。方法 本研究选取2019年3月—2020年12月在我院儿科住院并进行肺泡灌洗治疗的40例重症肺炎患儿作为研究对象。通过对这些患儿在感染急性期肺泡灌洗液中的细菌、真菌、肺炎支原体等进行病原学检查以及T 淋巴细胞亚群的检测,了解台山地区儿童重症肺炎病原体情况及耐药性、T淋巴细胞亚群与疾病严重程度、预后评估的关系。结果 BALF病原学检测结果分析中,肺炎支原体27例,肺炎支原体+肺炎链球菌5例,肺炎支原体+中间葡萄球菌2例,肺炎支原体+铅黄肠球菌1例,肺炎支原体+嗜麦芽假单胞菌2例,病原菌阴性3例;本组病例血清T细胞亚群检测结果显示:大部分病例CD3⁺、CD4⁺、CD8⁺及CD4⁺/CD8⁺水平有不同程度的下降。其中CD3⁺水平下降的有6例,CD4⁺水平下降的有16例,CD8+水平下降的有17例,CD4⁺、CD8⁺水平同时下降的有14例,CD3⁺、CD4⁺、CD8⁺水平同时下降的有4例;BALF细胞总数(3673.1±377.9)×10⁶ /L,巨噬细胞比例(23.6±17.6)%,淋巴细胞(22.1±16.2)%,中性粒细胞(46.5±24.8)%。结论 病原学分析儿童重症肺炎BALF的主要病原菌为肺炎支原体,血清T细胞亚群检测大多表现为CD4⁺、CD8⁺水平下降。

Objective To analyze the etiology of bronchoalveolar lavage fluid and prognosis of children with severe pneumonia. Methods In this study, 40 children with severe pneumonia who were hospitalized in the pediatrics department of our hospital and underwent alveolar lavage treatment from March 2019 to December 2020 were selected as the research objects. Through the detection of pathogens such as bacteria, fungi, Mycoplasma pneumoniae and T lymphocyte subsets of these children in the acute phase of infection, we can understand the pathogens and drug resistance of children with severe pneumonia in Taishan area and the relationship among drug resistance, T lymphocyte subsets and disease severity and prognosis assessment. Results In the analysis of the BALF pathogenic test results, there were 27 cases with Mycoplasma pneumoniae, 5 cases with Mycoplasma pneumoniae+Streptococcus pneumoniae, 2 cases with Mycoplasma pneumoniae+Staphylococcus intermedius, 1 case with Mycoplasma pneumoniae+Enterococcus casseliflavus, 2 cases with Mycoplasma pneumoniae+Pseudomonas maltophilia and 3 cases were pathogenic bacteria negative. The test results of serum T cell subsets of these cases showed that most of the cases had different degrees of decline in the levels of CD3⁺, CD4⁺, CD8⁺ and CD4⁺/CD8⁺. Among them, CD3⁺ levels decreased in 6 cases, CD4⁺ levels decreased in 16 cases, CD8⁺ levels decreased in 17 cases, CD4⁺ and CD8⁺ levels decreased in 14 cases, and CD3⁺, CD4⁺, and CD8⁺ levels decreased in 4 cases; total cell number of BALF was (3 673.1±377.9)×10⁶/L, the proportion of macrophages was (23.6±17.6)%, lymphocytes had (22.1±16.2)%, and neutrophils had (46.5±24.8)%. Conclusions Pathogenic analysis showed that the main pathogen of BALF in children with severe pneumonia is Mycoplasma pneumoniae, and the detection of serum T cell subsets mostly showed a decrease in CD4⁺ and CD8⁺ levels.