PDF(Pubmed)
Abstract：
Genome editing technologies, clustered regularly interspaced short palindromic repeats (CRISPR)-Cas in particular, have revolutionized the field of genetic engineering, providing promising avenues for treating various genetic diseases. Chronic kidney disease (CKD), a significant health concern affecting millions of individuals worldwide, can arise from either monogenic or polygenic mutations. With recent advancements in genomic sequencing, valuable insights into disease-causing mutations can be obtained, allowing for the development of new treatments for these genetic disorders. CRISPR-based treatments have emerged as potential therapies, especially for monogenic diseases, offering the ability to correct mutations and eliminate disease phenotypes. Innovations in genome editing have led to enhanced efficiency, specificity and ease of use, surpassing earlier editing tools such as zinc-finger nucleases and transcription activator-like effector nucleases (TALENs). Two prominent advancements in CRISPR-based gene editing are prime editing and base editing. Prime editing allows precise and efficient genome modifications without inducing double-stranded DNA breaks (DSBs), while base editing enables targeted changes to individual nucleotides in both RNA and DNA, promising disease correction in the absence of DSBs. These technologies have the potential to treat genetic kidney diseases through specific correction of disease-causing mutations, such as somatic mutations in PKD1 and PKD2 for polycystic kidney disease; NPHS1, NPHS2 and TRPC6 for focal segmental glomerulosclerosis; COL4A3, COL4A4 and COL4A5 for Alport syndrome; SLC3A1 and SLC7A9 for cystinuria and even VHL for renal cell carcinoma. Apart from editing the DNA sequence, CRISPR-mediated epigenome editing offers a cost-effective method for targeted treatment providing new avenues for therapeutic development, given that epigenetic modifications are associated with the development of various kidney disorders. However, there are challenges to overcome, including developing efficient delivery methods, improving safety and reducing off-target effects. Efforts to improve CRISPR-Cas technologies involve optimizing delivery vectors, employing viral and non-viral approaches and minimizing immunogenicity. With research in animal models providing promising results in rescuing the expression of wild-type podocin in mouse models of nephrotic syndrome and successful clinical trials in the early stages of various disorders, including cancer immunotherapy, there is hope for successful translation of genome editing to kidney diseases.
摘要：
基因组编辑技术,特别是成簇的规则间隔的短回文重复(CRISPR)-Cas，彻底改变了基因工程领域，为治疗各种遗传疾病提供了有希望的途径。慢性肾脏病(CKD),影响全球数百万人的重大健康问题，可以起因于单基因或多基因的突变。随着基因组测序的最新进展，可以获得对致病突变的有价值的见解，允许开发新的治疗这些遗传性疾病的方法。基于CRISPR的治疗已经成为潜在的治疗方法，尤其是单基因疾病，提供纠正突变和消除疾病表型的能力。基因组编辑的创新提高了效率，特异性和易用性，超越早期的编辑工具，如锌指核酸酶和转录激活因子样效应核酸酶（TALEN）。基于CRISPR的基因编辑的两个突出进步是prime编辑和base编辑。Prime编辑允许精确和有效的基因组修饰，而不会诱导双链DNA断裂（DSB）。虽然碱基编辑能够靶向改变RNA和DNA中的单个核苷酸，在没有DSB的情况下有希望的疾病矫正。这些技术有可能通过特定纠正致病突变来治疗遗传性肾病，如PKD1和PKD2的体细胞突变用于多囊肾病;NPHS1,NPHS2和TRPC6用于局灶节段肾小球硬化;COL4A3,COL4A4和COL4A5用于Alport综合征;SLC3A1和SLC7A9用于胱氨酸尿症,甚至VHL用于肾细胞癌。除了编辑DNA序列,CRISPR介导的表观基因组编辑为靶向治疗提供了一种经济有效的方法，为治疗开发提供了新的途径。鉴于表观遗传修饰与各种肾脏疾病的发展有关。然而,有挑战需要克服，包括开发有效的交付方法，提高安全性，减少脱靶效应。改进CRISPR-Cas技术的努力涉及优化递送载体，采用病毒和非病毒方法并最小化免疫原性。通过动物模型的研究，在挽救肾病综合征小鼠模型中野生型podocin的表达以及在各种疾病早期阶段的成功临床试验方面提供了有希望的结果，包括癌症免疫疗法，有希望将基因组编辑成功转化为肾脏疾病。
