Meshram Harsh Kumar, Gupta Sanjay Kumar, Gupta Akash, Nagori Kushagra
Department of Pharmacology, Rungta College of Pharmaceutical Sciences and Research, Kohka, Bhilai, Durg, Chhattisgarh 490024, India.
Department of Pharmacology, Rungta College of Pharmaceutical Sciences and Research, Kohka, Bhilai, Durg, Chhattisgarh 490024, India.
Ageing Res Rev. 2025 Sep;111:102851. doi: 10.1016/j.arr.2025.102851. Epub 2025 Aug 5.
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.
新兴的基因编辑技术，如CRISPR系统，为针对疾病的遗传和分子病因的精准医学提供了一条潜在途径。第二代CRISPR技术，包括碱基编辑、引导编辑和工程化Cas变体，提高了准确性，并为精确基因校正、转录抑制或激活以及神经退行性变病理途径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并调节神经炎症反应，所有这些都是阿尔茨海默病（AD）和帕金森病（PD）发病机制中不可或缺的部分，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，主要是姑息性的。临床前研究已经显示出有希望的结果，动物模型中的认知和运动缺陷有所改善。然而，必须解决重大挑战，以确保安全有效地递送至中枢神经系统，将脱靶效应降至最低，并解决伦理问题。当前的临床研究旨在将这些发现转化为可用的治疗选择。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，通过其独特优势提供治疗和研究能力。最终，转化神经基因组学的未来将决定基于CRISPR的策略在推进神经退行性疾病管理方面的临床可能性，从姑息性和对症治疗转向可行的疾病修饰机制形式。
