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CRISPR/Cas9:一种用于治疗肌萎缩侧索硬化症小鼠模型的基因组编辑技术。

CRISPR/Cas9 a genomic engineering technology for treatment in ALS mouse models.

作者信息

Khan Hamid, Riaz Hammad, Ahmed Adeel, Kiyani Mubin Mustafa, Jawad Sahibzada Muhammad, Ud Din Shah Syed Shahab, Abualait Turki, Al-Hussain Fawaz, Li Hong-Tao, Bashir Shahid

机构信息

Department of Geriatric Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.

Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, China.

出版信息

Regen Ther. 2025 Aug 13;30:575-583. doi: 10.1016/j.reth.2025.07.009. eCollection 2025 Dec.

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by the death of motor neurons in the spinal cord and brain regions, leading to a reduced survival rate in patients. Nearly 20 gene mutations are associated with ALS, with SOD1, FUS, TARDBP, and C9orf72 mutations being more common. Ninety percent of ALS cases are related to sporadic ALS, while the remaining 10 % are associated with familial ALS. CRISPR/Cas9, a genome engineering technology known as clustered regularly interspaced short palindromic repeats/CRISPR-associated system 9, has the potential for gene editing and for studying the underlying mechanisms of ALS in mouse models. This technique enables neuroscientists to reverse mutations found in ALS mouse models, providing new hope for understanding the complexities of ALS. Additionally, this tool can create mutations to probe the functional changes of genetic diseases. Using CRISPR/Cas9 with an in vivo delivery method involving adeno-associated vectors, it is possible to silence mutations in the SOD1-linked ALS mouse model. Some limitations related to CRISPR/Cas9 have been discussed in previous studies and need to be addressed before clinical trials can proceed. In this review-based study, we summarise the latest research on CRISPR/Cas9 genome editing for ALS in mouse models and discuss its limitations and future prospects as well.

摘要

肌萎缩侧索硬化症(ALS)是一种复杂的神经退行性疾病,其特征是脊髓和脑区的运动神经元死亡,导致患者生存率降低。近20种基因突变与ALS相关,其中超氧化物歧化酶1(SOD1)、融合蛋白(FUS)、反式激活反应DNA结合蛋白43(TARDBP)和9号染色体开放阅读框72(C9orf72)突变更为常见。90%的ALS病例与散发性ALS有关,其余10%与家族性ALS有关。CRISPR/Cas9是一种基因组工程技术,称为成簇规律间隔短回文重复序列/CRISPR相关系统9,具有基因编辑潜力,可用于研究小鼠模型中ALS的潜在机制。该技术使神经科学家能够逆转ALS小鼠模型中发现的突变,为理解ALS的复杂性带来了新希望。此外,该工具可以产生突变以探究遗传疾病的功能变化。使用CRISPR/Cas9并结合腺相关载体的体内递送方法,可以使与SOD1相关的ALS小鼠模型中的突变沉默。先前的研究已经讨论了与CRISPR/Cas9相关的一些局限性,在进行临床试验之前需要加以解决。在这项基于综述的研究中,我们总结了CRISPR/Cas9基因组编辑在小鼠模型中治疗ALS的最新研究,并讨论了其局限性和未来前景。

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