Suppr超能文献

酶替代疗法和造血干细胞移植:沃尔曼病治疗的新模式。

Enzyme replacement therapy and hematopoietic stem cell transplant: a new paradigm of treatment in Wolman disease.

机构信息

Department of Blood and Marrow Transplantation, Royal Manchester Children's Hospital, Oxford Road, Manchester, UK.

Department of Paediatric Histopathology, Royal Manchester Children's Hospital, Oxford Road, Manchester, UK.

出版信息

Orphanet J Rare Dis. 2021 May 21;16(1):235. doi: 10.1186/s13023-021-01849-7.

Abstract

BACKGROUND

Wolman disease is a rare, lysosomal storage disorder in which biallelic variants in the LIPA gene result in reduced or complete lack of lysosomal acid lipase. The accumulation of the substrates; cholesterol esters and triglycerides, significantly impacts cellular function. Untreated patients die within the first 12 months of life. Clinically, patients present severely malnourished, with diarrhoea and hepatosplenomegaly, many have an inflammatory phenotype, including with hemophagocytic lymphohistiocytosis (HLH). Hematopoietic stem cell transplant (HCT) had been historically the only treatment available but has a high procedure-related mortality because of disease progression and disease-associated morbidities. More recently, enzyme replacement therapy (ERT) with dietary substrate reduction (DSR) has significantly improved patient survival. However, ERT is life long, expensive and its utility is limited by anti-drug antibodies (ADA) and the need for central venous access.

RESULTS

We describe five Wolman disease patients diagnosed in infancy that were treated at Royal Manchester Children's Hospital receiving ERT with DSR then HCT-multimodal therapy. In 3/5 an initial response to ERT was attenuated by ADA with associated clinical and laboratory features of deterioration. 1/5 developed anaphylaxis to ERT and the other patient died post HCT with ongoing HLH. All patients received allogeneic HCT. 4/5 patients are alive, and both disease phenotype and laboratory parameters are improved compared to when they were on ERT alone. The gastrointestinal symptoms are particularly improved after HCT, with reduced diarrhoea and vomiting. This allows gradual structured normalisation of diet with improved tolerance of dietary fat. Histologically there are reduced cholesterol clefts, fewer foamy macrophages and an improved villous structure. Disease biomarkers also show improvement with ERT, immunotherapy and HCT. Three patients have mixed chimerism after HCT, indicating a likely engraftment-defect in this condition.

CONCLUSION

We describe combined ERT, DSR and HCT, multimodal treatment for Wolman disease. ERT and DSR stabilises the sick infant and reduces the formerly described prohibitively high, transplant-associated mortality in this condition. HCT abrogates the problems of ERT, namely attenuating ADA, the need for continuing venous access, and continuing high cost drug treatment. HCT also brings improved efficacy, particularly evident in improved gastrointestinal function and histology. Multimodal therapy should be considered a new paradigm of treatment for Wolman disease patients where there is an attenuated response to ERT, and for all patients where there is a well-matched transplant donor, in order to improve long term gut function, tolerance of a normal diet and quality of life.

摘要

背景

沃曼病是一种罕见的溶酶体贮积症,其双等位基因变异导致溶酶体酸性脂肪酶减少或完全缺乏。底物(胆固醇酯和甘油三酯)的积累显著影响细胞功能。未经治疗的患者在生命的头 12 个月内死亡。临床上,患者表现为严重营养不良,伴有腹泻和肝脾肿大,许多患者具有炎症表型,包括噬血细胞性淋巴组织细胞增生症(HLH)。造血干细胞移植(HCT)在历史上是唯一可用的治疗方法,但由于疾病进展和与疾病相关的发病率,其相关程序死亡率很高。最近,用饮食底物减少(DSR)进行酶替代疗法(ERT)显著提高了患者的生存率。然而,ERT 是终身的,昂贵的,并且由于抗药物抗体(ADA)和对中央静脉通路的需求,其效用受到限制。

结果

我们描述了在皇家曼彻斯特儿童医院接受治疗的 5 名在婴儿期被诊断为沃曼病的患者,他们接受了 ERT 联合 DSR 治疗,然后进行 HCT-多模式治疗。在 5 名患者中有 3 名患者的 ERT 初始反应因 ADA 而减弱,与疾病恶化相关的临床和实验室特征。1 名患者对 ERT 发生过敏反应,另一名患者在 HCT 后死亡,持续存在 HLH。所有患者均接受同种异体 HCT。4 名患者存活,与单独接受 ERT 相比,疾病表型和实验室参数均有所改善。HCT 后胃肠道症状明显改善,腹泻和呕吐减少。这允许逐渐正常化饮食,提高对脂肪的耐受性。组织学上,胆固醇裂隙减少,泡沫状巨噬细胞减少,绒毛结构改善。疾病生物标志物也显示出 ERT、免疫疗法和 HCT 的改善。3 名患者在 HCT 后出现混合嵌合体,表明该疾病存在可能的植入缺陷。

结论

我们描述了联合 ERT、DSR 和 HCT 的沃曼病多模式治疗。ERT 和 DSR 稳定了患病婴儿,并降低了该疾病中以前描述的高、与移植相关的死亡率。HCT 消除了 ERT 的问题,即减弱 ADA、对持续静脉通路的需求以及持续的高成本药物治疗。HCT 还带来了更好的疗效,特别是在改善胃肠道功能和组织学方面。对于对 ERT 反应减弱的沃曼病患者,以及所有有匹配的移植供体的患者,应考虑多模式治疗作为一种新的治疗方法,以改善长期肠道功能、对正常饮食的耐受性和生活质量。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/075b/8139039/b0bf0be9090a/13023_2021_1849_Fig1_HTML.jpg

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验