Heal thyself: The promise of autologous hematopoietic stem cell gene therapy in neurometabolic disorders.
Heal thyself: The promise of autologous hematopoietic stem cell gene therapy in neurometabolic disorders.
复制标题
治愈你自己：自体造血干细胞基因疗法在神经代谢疾病中的前景。
DOI：
10.1016/j.ymthe.2022.03.006
复制
发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Ahrens-Nicklas,RebeccaC
中科院分区：
文献类型：
--
作者：
Ahrens-Nicklas,RebeccaC
在过去的三十年中，针对先天性代谢错误（IEMs）患者，特别是溶酶体贮积病（lsd）患者的批准治疗方法数量迅速增长。不幸的是，尽管大多数患者患有中枢神经系统（CNS）疾病的严重负担，但大多数批准的治疗并不能改善神经系统症状。为了解决这一巨大的未满足的需求，针对许多疾病的脑导向基因治疗策略正在开发中。事实上，截至2021年6月，已经完成或正在进行的针对lsd中枢神经系统的基因治疗试验超过30项。最近，Fumagalli等人对atidarsagene autotemcel （arsa-cel）的安全性、有效性和耐久性进行了评估。2扩展了最初队列研究的有希望的结果。该研究结合了一项更大的开放标签I/II期研究和扩大准入计划的结果。研究人群包括29例早发性（婴儿晚期和青少年早期）患者，平均随访时间约为3年。安全性和有效性的结果都证明了这种治疗方法在偏色差性脑白质营养不良（MLD）中的前景。慢病毒造血干细胞基因疗法（HSCT-GT）治疗MLD的发展是一个早期的成功故事。这种进行性代谢性脑白质营养不良和LSD是由ARSA的致病变异引起的，ARSA编码芳基硫酸酯酶A，这是一种关键的细胞硫酸酯酶。ARSA活性的丧失导致神经系统中硫脂质的逐渐积累，引发脱髓鞘和神经变性。MLD严重程度的范围很广，晚期婴儿病例在30个月前出现，而青少年病例在30个月后出现。2020年，欧洲药品管理局（EMA）批准了ARSA -cel，这是一种基因疗法，包括用慢病毒载体编码人ARSA体外转导的自体造血干细胞和前体细胞，用于治疗症状前晚期婴儿或早期少年MLD，或症状早期少年MLD。此次批准是基于9例MLD患者的I/II期阳性试验。与未治疗的自然史对照组相比，该初始队列显示疾病生化指标和神经系统预后改善。然而，本研究的规模和随访时间有限。
Over the past three decades, the number of approved therapies for patients with inborn errors of metabolism (IEMs), especially lysosomal storage diseases (LSDs), has grown rapidly. Unfortunately, most approved treatments do not improve neurologic symptoms, even though most patients suffer from a severe burden of central nervous system (CNS) disease. To address this large unmet need, brain-directed gene therapy strategies are under development for many IEMs. In fact, as of June 2021, there were more than 30 completed or ongoing gene therapy trials targeting the CNS in LSDs. 1 Most recently, an evaluation of atidarsagene autotemcel (arsa-cel) safety, efficacy, and durability by Fumagalli et al. 2 expands upon promising results from an initial cohort. The study combines results from a larger open-label Phase I/II study and expanded access program. The study population comprised 29 early-onset (late-infantile and early-juvenile) patients with a mean duration of follow-up of approximately 3 years. Both the safety and efficacy results demonstrate the promise of this therapeutic approach in metachromatic leukodystrophy (MLD).The development of lentiviral hematopoietic stem-cell gene therapy (HSCT-GT) for MLD has been an early success story. This progressive metabolic leukodystrophy and LSD arises from pathogenic variants in ARSA, which encodes arylsulfatase A, a key cellular sulfatase. Loss of ARSA activity leads to the progressive accumulation of sulfatides in the nervous system, triggering demyelination and neurodegeneration. There is a broad spectrum of MLD severity, with late-infantile cases presenting before 30 months of age as opposed to juvenile cases that present after this age. In 2020, the European Medicines Agency (EMA) approved arsa-cel, a gene therapy comprising autologous hematopoietic stem and precursor cells transduced ex vivo with a lentiviral vector encoding human ARSA, for the treatment of pre-symptomatic late-infantile or early-juvenile MLD, or early-symptomatic early-juvenile MLD. This approval was based on a positive Phase I/II trial in 9 MLD patients. 3 This initial cohort demonstrated improved biochemical markers of disease and neurologic outcomes as compared to untreated natural history controls. However, this study was limited in both size and duration of follow-up.