新一代CRISPR基因编辑工具精准治疗阿尔茨海默病和帕金森病

IF 12.4 1区 医学 Q1 CELL BIOLOGY
Harsh Kumar Meshram , Sanjay Kumar Gupta , Akash Gupta , Kushagra Nagori , Ajazuddin
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引用次数: 0

摘要

新兴的基因编辑技术,如CRISPR系统,代表了针对疾病的遗传和分子原因的精准医学的潜在途径。第二代CRISPR技术,包括碱基编辑、引物编辑和工程Cas变体,提高了保真度,并为精确的基因校正、转录抑制或激活以及神经退行性疾病病理通路的调节提供了替代策略。这些工具可以纠正单核苷酸突变,减少病理性蛋白质积累,调节神经炎症反应,这些都是阿尔茨海默病(AD)和帕金森病(PD)的发病机制所必需的,这两种疾病都是慢性进行性神经退行性疾病。不幸的是,目前可用的治疗方法有限,而且主要是姑息性的。临床前研究已经显示出有希望的结果,在动物模型中改善了认知和运动缺陷。然而,必须解决重大挑战,以确保安全有效地向中枢神经系统输送,最大限度地减少脱靶效应,并解决伦理问题。目前的临床研究旨在将这些发现转化为可用的治疗方案。本综述还确定了下一代CRISPR系统作为AD和PD背景下的工具的生物学机制、治疗用例和当前局限性,通过其独特的优势提供治疗和研究能力。最终,交易性神经基因组学的未来将决定基于crispr的策略的临床可能性,以推进神经退行性疾病的管理,超越姑息性和对症治疗,走向可行的疾病改造机制形式。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Next-generation CRISPR gene editing tools in the precision treatment of Alzheimer’s and Parkinson’s disease
Emerging gene-editing technologies, such as the CRISPR system, represent a potential pathway for precision medicine targeting the genetic and molecular causes of diseases. Second-generation CRISPR technologies, including base editing, prime editing, and engineered Cas variants, have improved fidelity and offer alternative strategies for precise gene correction, transcriptional repression or activation, and modulation of pathological pathways in neurodegeneration. These tools can correct single-nucleotide mutations, reduce pathological protein accumulation, and modulate neuroinflammatory responses, all integral to the pathogenesis of Alzheimer’s disease (AD) and Parkinson’s disease (PD), both chronic, progressive neurodegenerative disorders. Unfortunately, currently available treatments are limited and primarily palliative. Preclinical studies have shown promising results, with improvements in cognitive and motor deficits in animal models. However, significant challenges must be addressed to ensure safe and effective delivery to the CNS, minimize off-target effects, and address ethical concerns. Current clinical investigations aim to translate these findings into available therapeutic options. This review also identifies the biological mechanisms, therapeutic use cases, and current limitations of next-generation CRISPR systems as tools in the context of AD and PD, providing both therapeutic and research capabilities through their unique strengths. Ultimately, the future of transactional neurogenomics will determine the clinical possibilities of CRISPR-based strategies for advancing neurodegenerative disease management beyond palliative and symptomatic treatment, toward a feasible mechanistic form of disease modification.
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来源期刊
Ageing Research Reviews
Ageing Research Reviews 医学-老年医学
CiteScore
19.80
自引率
2.30%
发文量
216
审稿时长
55 days
期刊介绍: With the rise in average human life expectancy, the impact of ageing and age-related diseases on our society has become increasingly significant. Ageing research is now a focal point for numerous laboratories, encompassing leaders in genetics, molecular and cellular biology, biochemistry, and behavior. Ageing Research Reviews (ARR) serves as a cornerstone in this field, addressing emerging trends. ARR aims to fill a substantial gap by providing critical reviews and viewpoints on evolving discoveries concerning the mechanisms of ageing and age-related diseases. The rapid progress in understanding the mechanisms controlling cellular proliferation, differentiation, and survival is unveiling new insights into the regulation of ageing. From telomerase to stem cells, and from energy to oxyradical metabolism, we are witnessing an exciting era in the multidisciplinary field of ageing research. The journal explores the cellular and molecular foundations of interventions that extend lifespan, such as caloric restriction. It identifies the underpinnings of manipulations that extend lifespan, shedding light on novel approaches for preventing age-related diseases. ARR publishes articles on focused topics selected from the expansive field of ageing research, with a particular emphasis on the cellular and molecular mechanisms of the aging process. This includes age-related diseases like cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. The journal also covers applications of basic ageing research to lifespan extension and disease prevention, offering a comprehensive platform for advancing our understanding of this critical field.
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