意大利圣拉斐尔科学研究所Alessandro Aiuti团队研究了造血干祖细胞基因治疗Hurler综合征的效果。2021年11月17日，《新英格兰医学杂志》发表了这一成果。

异基因造血干细胞移植是Hurler综合征（粘多糖病I型，Hurler变体[MPSIH]）的标准治疗方法。然而，这种治疗只能部分治愈，并伴有并发症。

该研究涉及8名患有MPSIH的儿童。在登记时，这些儿童缺乏合适的异基因供体，发育商或智商得分高于70（即，没有一个儿童有中度或重度认知障碍）。这些儿童在清髓性预处理后接受了用α-L-碘尿苷酶（IDUA）编码的慢病毒载体体外转导的自体造血干祖细胞（HSPC）。主要终点是安全性和纠正血液IDUA活性至超生理水平。溶酶体储存物质的清除以及骨骼和神经生理发育被评估为次要和探索性终点。该研究计划为期5年。

研究组报告了中期结果。HSPC基因治疗时儿童的平均年龄为1.9岁。中位随访2.10年后，该手术的安全性与已知的自体造血干细胞移植相似。所有患者均表现出迅速和持续的基因校正细胞植入，并在一个月内具有超生理血液IDUA活性，该活性一直维持到最近随访。

可评估的5名患者中有4名尿糖胺聚糖（GAG）排泄量急剧下降，在12个月时达到正常水平。先前无法检测到脑脊液中IDUA活性水平的患者在基因治疗后变得可检测，并与GAG的局部清除有关。患者表现出稳定的认知能力、与持续运动发育相对应的稳定运动技能、改善或稳定的大脑和脊柱磁共振成像结果、关节僵硬减轻以及符合世界卫生组织生长图表的正常生长。

研究结果表明，在MPSIH患者中进行HSPC基因治疗可导致周围组织和中枢神经系统的广泛代谢纠正。

附：英文原文

Title: Hematopoietic Stem- and Progenitor-Cell Gene Therapy for Hurler Syndrome

Author: Bernhard Gentner, M.D.,, Francesca Tucci, M.D.,, Stefania Galimberti, Ph.D.,, Francesca Fumagalli, M.D.,, Maurizio De Pellegrin, M.D.,, Paolo Silvani, M.D.,, Chiara Camesasca, M.D.,, Silvia Pontesilli, M.D.,, Silvia Darin, R.N.,, Francesca Ciotti, Psy.D.,, Marina Sarzana, P.T.,, Giulia Consiglieri, M.D.,, Chiara Filisetti, M.D.,, Giulia Forni, B.Sc.,, Laura Passerini, Ph.D.,, Daniela Tomasoni, B.Sc.,, Daniela Cesana, Ph.D.,, Andrea Calabria, Ph.D.,, Giulio Spinozzi, Ph.D.,, Maria-Pia Cicalese, M.D., Ph.D.,, Valeria Calbi, M.D.,, Maddalena Migliavacca, M.D., Ph.D.,, Federica Barzaghi, M.D., Ph.D.,, Francesca Ferrua, M.D., Ph.D.,, Vera Gallo, M.D.,, Simona Miglietta, M.Sc.,, Erika Zonari, Ph.D.,, Patali S. Cheruku, M.D.,, Claudia Forni, Ph.D.,, Marcella Facchini, Ph.D.,, Ambra Corti, B.Sc.,, Michela Gabaldo, Pharm.D.,, Stefano Zancan, M.Sc.,, Serena Gasperini, M.D.,, Attilio Rovelli, M.D.,, Jaap-Jan Boelens, M.D., Ph.D.,, Simon A. Jones, M.D.,, Robert Wynn, M.D.,, Cristina Baldoli, M.D.,, Eugenio Montini, Ph.D.,, Silvia Gregori, Ph.D.,, Fabio Ciceri, M.D.,, Maria G. Valsecchi, Ph.D.,, Giancarlo la Marca, Pharm.Sc.,, Rossella Parini, M.D.,, Luigi Naldini, M.D., Ph.D.,, Alessandro Aiuti, M.D., Ph.D.,, and Maria-Ester Bernardo, M.D., Ph.D.

Issue&Volume: 2021-11-17

Abstract:

Background

Allogeneic hematopoietic stem-cell transplantation is the standard of care for Hurler syndrome (mucopolysaccharidosis type I, Hurler variant [MPSIH]). However, this treatment is only partially curative and is associated with complications.

Methods

We are conducting an ongoing study involving eight children with MPSIH. At enrollment, the children lacked a suitable allogeneic donor and had a Developmental Quotient or Intelligence Quotient score above 70 (i.e., none had moderate or severe cognitive impairment). The children received autologous hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with an α-L-iduronidase (IDUA)–encoding lentiviral vector after myeloablative conditioning. Safety and correction of blood IDUA activity up to supraphysiologic levels were the primary end points. Clearance of lysosomal storage material as well as skeletal and neurophysiological development were assessed as secondary and exploratory end points. The planned duration of the study is 5 years.

Results

We now report interim results. The children’s mean (±SD) age at the time of HSPC gene therapy was 1.9±0.5 years. At a median follow-up of 2.10 years, the procedure had a safety profile similar to that known for autologous hematopoietic stem-cell transplantation. All the patients showed prompt and sustained engraftment of gene-corrected cells and had supraphysiologic blood IDUA activity within a month, which was maintained up to the latest follow-up. Urinary glycosaminoglycan (GAG) excretion decreased steeply, reaching normal levels at 12 months in four of five patients who could be evaluated. Previously undetectable levels of IDUA activity in the cerebrospinal fluid became detectable after gene therapy and were associated with local clearance of GAGs. Patients showed stable cognitive performance, stable motor skills corresponding to continued motor development, improved or stable findings on magnetic resonance imaging of the brain and spine, reduced joint stiffness, and normal growth in line with World Health Organization growth charts.

Conclusions

The delivery of HSPC gene therapy in patients with MPSIH resulted in extensive metabolic correction in peripheral tissues and the central nervous system.

DOI: 10.1056/NEJMoa2106596

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2106596