意大利圣拉斐尔科学研究所Alessandro Aiuti团队研究了慢病毒造血干细胞基因治疗早发异染性脑白质营养不良的疗效。该项研究成果发表在2022年1月22日出版的《柳叶刀》杂志上。

现有医疗对异染性脑白质营养不良（MLD）尚无有效治疗方案。研究组分析了atidarsagene autotemcel（arsa-cel） 治疗MLD患者的安全性和有效性。

该研究是一项前瞻性、非随机、1/2期临床研究和扩大访问框架结果的综合分析。研究组招募了29例有症状前或早期症状的早发MLD患儿，经生化和分子诊断证实，接受arsa cel治疗，即一种包含自体造血干祖细胞（HSPC）群的基因疗法，使用编码人芳基硫酸酯酶A（ARSA）cDNA的慢病毒载体进行体外转导，并与未经治疗的自然史（NHx）队列（31名早发MLD患者，年龄和疾病亚型相匹配）进行比较。

患者在意大利米兰接受治疗和随访。共同疗效终点为治疗组患者治疗后2年的总体运动功能测量总分与对照组相比改善10%以上，治疗后2年的总外周血单核细胞（PBMC）ARSA活性基线值与治疗前的改善。

在分析时，26名接受ARSA细胞治疗的患者存活，中位随访时间为3.16年。两名患者死于疾病进展，一名患者死于被认为与治疗无关的突发事件。经过白消安预处理后，所有ARSA细胞治疗的患者都显示出持续转基因HSPC的多系移植。

治疗2年后，晚期婴儿型变异体患者外周血单核细胞ARSA活性显著高于基线水平，平均增加18.7倍，早期少年型变异体患者ARSA活性平均增加5.7倍，与基线相比差异均显著。

治疗2年后，接受治疗的患者与年龄匹配和疾病亚型匹配的NHx患者之间的粗大运动功能测量总分的平均差异对于晚期婴儿型MLD（66%）和早期少年型MLD（42%）患者均具有显著性。

大多数接受治疗的患者在健康儿童的预期范围内逐步获得运动技能，或运动能力稳定（保持行走能力）。此外，大多数患者在整个随访过程中表现出正常的认知发展和预防或延迟中枢和外周脱髓鞘和脑萎缩；在症状出现之前接受治疗的患者中，治疗益处尤其明显。

患者的输注耐受性良好，没有证据显示异常克隆增殖或复制能力强的慢病毒。所有患者至少有一次3级及以上不良事件；大多数与条件反射或背景疾病有关。与ARSA细胞相关的唯一不良事件是4名患者出现短暂的抗ARSA抗体，但并不影响临床结局。

研究结果表明，arsa-cel治疗通过保留大多数患者的认知功能和运动发育，减缓脱髓鞘和脑萎缩，对早发MLD儿童产生了持续的临床相关益处。

附：英文原文

Title: Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded access

Author: Francesca Fumagalli, Valeria Calbi, Maria Grazia Natali Sora, Maria Sessa, Cristina Baldoli, Paola Maria V Rancoita, Francesca Ciotti, Marina Sarzana, Maddalena Fraschini, Alberto Andrea Zambon, Serena Acquati, Daniela Redaelli, Vanessa Attanasio, Simona Miglietta, Fabiola De Mattia, Federica Barzaghi, Francesca Ferrua, Maddalena Migliavacca, Francesca Tucci, Vera Gallo, Ubaldo Del Carro, Sabrina Canale, Ivana Spiga, Laura Lorioli, Salvatore Recupero, Elena Sophia Fratini, Francesco Morena, Paolo Silvani, Maria Rosa Calvi, Marcella Facchini, Sara Locatelli, Ambra Corti, Stefano Zancan, Gigliola Antonioli, Giada Farinelli, Michela Gabaldo, Jesus Garcia-Segovia, Laetitia C Schwab, Gerald F Downey, Massimo Filippi, Maria Pia Cicalese, Sabata Martino, Clelia Di Serio, Fabio Ciceri, Maria Ester Bernardo, Luigi Naldini, Alessandra Biffi, Alessandro Aiuti

Issue&Volume: 2022/01/22

Abstract:

Background

Effective treatment for metachromatic leukodystrophy (MLD) remains a substantial unmet medical need. In this study we investigated the safety and efficacy of atidarsagene autotemcel (arsa-cel) in patients with MLD.

Methods

This study is an integrated analysis of results from a prospective, non-randomised, phase 1/2 clinical study and expanded-access frameworks. 29 paediatric patients with pre-symptomatic or early-symptomatic early-onset MLD with biochemical and molecular confirmation of diagnosis were treated with arsa-cel, a gene therapy containing an autologous haematopoietic stem and progenitor cell (HSPC) population transduced ex vivo with a lentiviral vector encoding human arylsulfatase A (ARSA) cDNA, and compared with an untreated natural history (NHx) cohort of 31 patients with early-onset MLD, matched by age and disease subtype. Patients were treated and followed up at Ospedale San Raffaele, Milan, Italy. The coprimary efficacy endpoints were an improvement of more than 10% in total gross motor function measure score at 2 years after treatment in treated patients compared with controls, and change from baseline of total peripheral blood mononuclear cell (PBMC) ARSA activity at 2 years after treatment compared with values before treatment. This phase 1/2 study is registered with ClinicalTrials.gov, NCT01560182.

Findings

At the time of analyses, 26 patients treated with arsa-cel were alive with median follow-up of 3·16 years (range 0·64–7·51). Two patients died due to disease progression and one due to a sudden event deemed unlikely to be related to treatment. After busulfan conditioning, all arsa-cel treated patients showed sustained multilineage engraftment of genetically modified HSPCs. ARSA activity in PBMCs was significantly increased above baseline 2 years after treatment by a mean 18·7-fold (95% CI 8·3–42·2; p<0·0001) in patients with the late-infantile variant and 5·7-fold (2·6–12·4; p<0·0001) in patients with the early-juvenile variant. Mean differences in total scores for gross motor function measure between treated patients and age-matched and disease subtype-matched NHx patients 2 years after treatment were significant for both patients with late-infantile MLD (66% [95% CI 48·9–82·3]) and early-juvenile MLD (42% [12·3–71·8]). Most treated patients progressively acquired motor skills within the predicted range of healthy children or had stabilised motor performance (maintaining the ability to walk). Further, most displayed normal cognitive development and prevention or delay of central and peripheral demyelination and brain atrophy throughout follow-up; treatment benefits were particularly apparent in patients treated before symptom onset. The infusion was well tolerated and there was no evidence of abnormal clonal proliferation or replication-competent lentivirus. All patients had at least one grade 3 or higher adverse event; most were related to conditioning or to background disease. The only adverse event related to arsa-cel was the transient development of anti-ARSA antibodies in four patients, which did not affect clinical outcomes.

Interpretation

Treatment with arsa-cel resulted in sustained, clinically relevant benefits in children with early-onset MLD by preserving cognitive function and motor development in most patients, and slowing demyelination and brain atrophy.

DOI: 10.1016/S0140-6736(21)02017-1

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02017-1/fulltext