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精准行动:成簇规律间隔短回文重复序列/CRISPR相关蛋白在基因治疗中的作用

Precision in Action: The Role of Clustered Regularly Interspaced Short Palindromic Repeats/Cas in Gene Therapies.

作者信息

Banda Amrutha, Impomeni Olivia, Singh Aparana, Baloch Abdul Rasheed, Hu Wenhui, Jaijyan Dabbu Kumar

机构信息

Department of Biology, The College of New Jersey, Ewing Township, NJ 08618, USA.

Department of Chemistry, National Institute of Technology Agartala, Agartala 799046, India.

出版信息

Vaccines (Basel). 2024 Jun 7;12(6):636. doi: 10.3390/vaccines12060636.

Abstract

Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated enzyme-CAS holds great promise for treating many uncured human diseases and illnesses by precisely correcting harmful point mutations and disrupting disease-causing genes. The recent Food and Drug Association (FDA) approval of the first CRISPR-based gene therapy for sickle cell anemia marks the beginning of a new era in gene editing. However, delivering CRISPR specifically into diseased cells in vivo is a significant challenge and an area of intense research. The identification of new CRISPR/Cas variants, particularly ultra-compact CAS systems with robust gene editing activities, paves the way for the low-capacity delivery vectors to be used in gene therapies. CRISPR/Cas technology has evolved beyond editing DNA to cover a wide spectrum of functionalities, including RNA targeting, disease diagnosis, transcriptional/epigenetic regulation, chromatin imaging, high-throughput screening, and new disease modeling. CRISPR/Cas can be used to engineer B-cells to produce potent antibodies for more effective vaccines and enhance CAR T-cells for the more precise and efficient targeting of tumor cells. However, CRISPR/Cas technology has challenges, including off-target effects, toxicity, immune responses, and inadequate tissue-specific delivery. Overcoming these challenges necessitates the development of a more effective and specific CRISPR/Cas delivery system. This entails strategically utilizing specific gRNAs in conjunction with robust CRISPR/Cas variants to mitigate off-target effects. This review seeks to delve into the intricacies of the CRISPR/Cas mechanism, explore progress in gene therapies, evaluate gene delivery systems, highlight limitations, outline necessary precautions, and scrutinize the ethical considerations associated with its application.

摘要

成簇规律间隔短回文重复序列(CRISPR)相关酶-CAS有望通过精确纠正有害点突变和破坏致病基因来治疗许多未治愈的人类疾病。美国食品药品监督管理局(FDA)最近批准了首个用于镰状细胞贫血的基于CRISPR的基因疗法,标志着基因编辑新时代的开始。然而,在体内将CRISPR特异性递送至患病细胞是一项重大挑战,也是一个深入研究的领域。新型CRISPR/Cas变体的鉴定,特别是具有强大基因编辑活性的超紧凑型CAS系统,为基因治疗中使用的低容量递送载体铺平了道路。CRISPR/Cas技术已从编辑DNA发展到涵盖广泛的功能,包括RNA靶向、疾病诊断、转录/表观遗传调控、染色质成像、高通量筛选和新的疾病建模。CRISPR/Cas可用于改造B细胞以产生强效抗体用于更有效的疫苗,并增强嵌合抗原受体(CAR)T细胞以更精确高效地靶向肿瘤细胞。然而,CRISPR/Cas技术存在挑战,包括脱靶效应、毒性、免疫反应和组织特异性递送不足。克服这些挑战需要开发更有效、更特异的CRISPR/Cas递送系统。这需要策略性地利用特定的引导RNA(gRNA)与强大的CRISPR/Cas变体相结合,以减轻脱靶效应。本综述旨在深入探讨CRISPR/Cas机制的复杂性,探索基因治疗的进展,评估基因递送系统,突出局限性,概述必要的预防措施,并审视与其应用相关的伦理考量。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16b7/11209408/0204921f864a/vaccines-12-00636-g001.jpg

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