摘要
继γ逆转录病毒基因治疗(GT)和患者造血干细胞移植抢救后,我们报告了一系列导致长期存活和小儿伴X染色体遗传的慢性肉芽肿病(X-CGD)的治疗事件。由于危及生命的感染难以治疗,则需要造血干细胞移植(HSCT),但没有相匹配的HLA捐助者,我们采用GT手段对患有X-CGD的2个男孩进行治疗。2个男孩经GT治疗,彻底解决了侵袭性曲霉感染问题。然而,一个孩子发展为骨髓增生异常综合征(MDS),由亲嗜性病毒整合位点1(EVI1)、信号转导和基因转录激活因子3(STAT3)双插入激活引起。尽管对清髓性预处理异基因造血干细胞移植抵抗,但经二次强化救援异基因造血干细胞移植导致了100%的供者嵌合现象和MDS消失。另一个孩子没有发展为骨质增生异常综合(MDS),而是经早期的标准异基因造血干细胞移植得以治愈,尽管将MDS1基因单独插入进行克隆扩增。MDS1-Evi1克隆整合技术的缓慢发展可能为临床干预提供指导,即在恶变前进行异基因造血干细胞移植。GT对儿童生存和难治性感染的清除必不可少,未来携带更安全的慢病毒自灭活(SIN)载体GT可能为患有致死感染或缺乏HLA相匹配的造血干细胞的X-CGD患者提供一种替代治疗。
关键词: 异基因造血干细胞移植,慢性肉芽肿病,亲嗜性病毒整合位点1,基因治疗,原发性免疫缺陷,逆转录病毒载体,STAT3,转录激活
Current Gene Therapy
Title:Successful Combination of Sequential Gene Therapy and Rescue Allo-HSCT in Two Children with X-CGD - Importance of Timing
Volume: 15 Issue: 4
Author(s): Ulrich Siler, Anna Paruzynski, Heidi Holtgreve-Grez, Elena Kuzmenko, Ulrike Koehl, Eleonore D. Renner, Canan Alhan, , Arjan A. van de Loosdrecht, Joachim Schwäble, Thomas Pfluger, Joelle Tchinda, Markus Schmugge, Anna Jauch, Sonja Naundorf, Klaus Kühlcke, Gundula Notheis, Tayfun Güngor, Christof v. Kalle, Manfred Schmidt and Manuel Grez, Reinhard Seger and Janine Reichenbach
Affiliation:
关键词: 异基因造血干细胞移植,慢性肉芽肿病,亲嗜性病毒整合位点1,基因治疗,原发性免疫缺陷,逆转录病毒载体,STAT3,转录激活
摘要: We report on a series of sequential events leading to long-term survival and cure of pediatric X-linked chronic granulomatous disease (X-CGD) patients after gamma-retroviral gene therapy (GT) and rescue HSCT. Due to therapyrefractory life-threatening infections requiring hematopoietic stem cell transplantation (HSCT) but absence of HLAidentical donors, we treated 2 boys with X-CGD by GT. Following GT both children completely resolved invasive Aspergillus nidulans infections. However, one child developed dual insertional activation of ecotropic viral integration site 1 (EVI1) and signal transducer and activator of transcription 3 (STAT3) genes, leading to myelodysplastic syndrome (MDS) with monosomy 7. Despite resistance to mismatched allo-HSCT with standard myeloablative conditioning, secondary intensified rescue allo-HSCT resulted in 100 % donor chimerism and disappearance of MDS. The other child did not develop MDS despite expansion of a clone with a single insertion in the myelodysplasia syndrome 1 (MDS1) gene and was cured by early standard allo-HSCT. The slowly developing dominance of clones harboring integrations in MDS1-EVI1 may guide clinical intervention strategies, i.e. early rescue allo-HSCT, prior to malignant transformation. GT was essential for both children to survive and to clear therapy-refractory infections, and future GT with safer lentiviral self-inactivated (SIN) vectors may offer a therapeutic alternative for X-CGD patients suffering from life-threatening infections and lacking HLA-identical HSC donors.
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Ulrich Siler, Anna Paruzynski, Heidi Holtgreve-Grez, Elena Kuzmenko, Ulrike Koehl, Eleonore D. Renner, Canan Alhan , , Arjan A. van de Loosdrecht, Joachim Schwäble, Thomas Pfluger, Joelle Tchinda, Markus Schmugge, Anna Jauch , Sonja Naundorf, Klaus Kühlcke, Gundula Notheis, Tayfun Güngor, Christof v. Kalle, Manfred Schmidt and Manuel Grez, Reinhard Seger and Janine Reichenbach , Successful Combination of Sequential Gene Therapy and Rescue Allo-HSCT in Two Children with X-CGD - Importance of Timing, Current Gene Therapy 2015; 15 (4) . https://dx.doi.org/10.2174/1566523215666150515145255
DOI https://dx.doi.org/10.2174/1566523215666150515145255 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
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