临床前慢病毒载体介导的造血干细胞和祖细胞基因疗法可纠正庞贝病相关的肌肉和神经系统表现。

IF 12.1 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Molecular Therapy Pub Date : 2024-11-06 Epub Date: 2024-09-17 DOI:10.1016/j.ymthe.2024.09.024
John K Yoon, Jeffrey W Schindler, Mariana Loperfido, Cristina Baricordi, Mark P DeAndrade, Mary E Jacobs, Christopher Treleaven, Robert N Plasschaert, Aimin Yan, Cecilia N Barese, Yildirim Dogan, Vicky Ping Chen, Claudia Fiorini, Fritz Hull, Luigi Barbarossa, Zeenath Unnisa, Daniel Ivanov, Robert H Kutner, Swaroopa Guda, Christine Oborski, Tim Maiwald, Véronique Michaud, Michael Rothe, Axel Schambach, Richard Pfeifer, Chris Mason, Luca Biasco, Niek P van Til
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引用次数: 0

摘要

庞贝氏症是一种罕见的遗传性神经肌肉疾病,由酸性α-葡萄糖苷酶(GAA)缺乏引起,会导致糖原在溶酶体中积聚,从而导致肌肉逐渐变得无力。目前的标准治疗方法是酶替代疗法(ERT),但这种疗法并不能治愈疾病,而且存在一些局限性,如对骨骼肌、中枢神经系统和外周神经系统的渗透性较差,存在对重组酶产生免疫反应的风险,以及需要大剂量和频繁输液等。为了克服这些局限性,有人提出了慢病毒载体介导的造血干细胞和祖细胞(HSPC)基因疗法,作为治疗庞贝氏症的新一代方法。本研究证明了慢病毒 HSPC 基因疗法在临床前小鼠模型中逆转庞贝氏症病理效应的潜力。它包括通过整合位点分析进行全面的安全性评估,以及对中枢神经组织样本进行单细胞RNA测序分析,以深入了解表型矫正的潜在机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Preclinical lentiviral hematopoietic stem cell gene therapy corrects Pompe disease-related muscle and neurological manifestations.

Pompe disease, a rare genetic neuromuscular disorder, is caused by a deficiency of acid alpha-glucosidase (GAA), leading to an accumulation of glycogen in lysosomes, and resulting in the progressive development of muscle weakness. The current standard treatment, enzyme replacement therapy (ERT), is not curative and has limitations such as poor penetration into skeletal muscle and both the central and peripheral nervous systems, a risk of immune responses against the recombinant enzyme, and the requirement for high doses and frequent infusions. To overcome these limitations, lentiviral vector-mediated hematopoietic stem and progenitor cell (HSPC) gene therapy has been proposed as a next-generation approach for treating Pompe disease. This study demonstrates the potential of lentiviral HSPC gene therapy to reverse the pathological effects of Pompe disease in a preclinical mouse model. It includes a comprehensive safety assessment via integration site analysis, along with single-cell RNA sequencing analysis of central nervous tissue samples to gain insights into the underlying mechanisms of phenotype correction.

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来源期刊
Molecular Therapy
Molecular Therapy 医学-生物工程与应用微生物
CiteScore
19.20
自引率
3.20%
发文量
357
审稿时长
3 months
期刊介绍: Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.
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