CRISPR-Cas system permanently deletes any harmful gene-of-interest to combat cancer growth.Chitosan(CS)is a potential cancer therapeutic that mediates via PI3K/Akt/mTOR,MAPK and NF-kβsignaling pathway modulation.CS a...CRISPR-Cas system permanently deletes any harmful gene-of-interest to combat cancer growth.Chitosan(CS)is a potential cancer therapeutic that mediates via PI3K/Akt/mTOR,MAPK and NF-kβsignaling pathway modulation.CS and its covalent derivatives have been designed as nanocarrier of CRISPR-Cas9 alone(plasmid or ribonucleoprotein)or in combination with chemical drug for cancer treatment.The nanocarrier was functionalized with polyethylene glycol(PEG),targeting ligand,cell penetrating ligand and its inherent positive zeta potential to mitigate premature clearance and particulate aggregation,and promote cancer cell/nucleus targeting and permeabilization to enable CRISPR-Cas9 acting on the host DNA.Different physicochemical attributes are required for the CS-based nanocarrier to survive from the administration site,through the systemic circulation-extracellular matrix-mucus-mucosa axis,to the nucleus target.CRISPR-Cas9 delivery is met with heterogeneous uptake by the cancer cells.Choice of excipients such as targeting ligand and PEG may be inappropriate due to lacking overexpressed cancer receptor or availability of excessive metabolizing enzyme and immunoglobulin that defies the survival and action of these excipients rendering nanocarrier fails to reach the target site.Cancer omics analysis should be implied to select excipients which meet the pathophysiological needs,and chitosan nanocarrier with a“transformative physicochemical behavior”is essential to succeed CRISPR-Cas9 delivery.展开更多
文摘基因治疗作为生物医学领域的一项变革性进展,利用基因编辑技术和载体传递手段修复或替代缺陷基因,在医学研究和临床应用中展现出了巨大的潜力。近年来,随着成簇规则间隔的短回文重复序列及其相关蛋白9(Clustered Regularly Interspaced Short Palindromic Repeat/CRISPR-Associated Protein 9,CRISPR-Cas9)技术的重大突破、非病毒载体的持续改进及政策支持的不断增强,基因治疗的应用范围已从传统的单基因遗传病扩展至肿瘤、慢性病及感染性疾病等多个领域,显示出广泛的应用前景。尽管基因治疗已经取得显著进展,但仍面临安全性、有效性、伦理问题及治疗费用高昂等诸多挑战,极大地限制了其临床应用潜力。该文旨在基于CRISPR-Cas9技术探讨基因治疗技术的创新及发展趋势,通过分析当前的研究进展和临床应用,发掘基因治疗在遗传性疾病、癌症及罕见病等治疗中的潜力,并讨论该技术在未来研究中的发展方向,以期为相关领域的研究提供工具。
基金MOHE (FRGS/1/2023/STG05/UITM/01/3) for funding support
文摘CRISPR-Cas system permanently deletes any harmful gene-of-interest to combat cancer growth.Chitosan(CS)is a potential cancer therapeutic that mediates via PI3K/Akt/mTOR,MAPK and NF-kβsignaling pathway modulation.CS and its covalent derivatives have been designed as nanocarrier of CRISPR-Cas9 alone(plasmid or ribonucleoprotein)or in combination with chemical drug for cancer treatment.The nanocarrier was functionalized with polyethylene glycol(PEG),targeting ligand,cell penetrating ligand and its inherent positive zeta potential to mitigate premature clearance and particulate aggregation,and promote cancer cell/nucleus targeting and permeabilization to enable CRISPR-Cas9 acting on the host DNA.Different physicochemical attributes are required for the CS-based nanocarrier to survive from the administration site,through the systemic circulation-extracellular matrix-mucus-mucosa axis,to the nucleus target.CRISPR-Cas9 delivery is met with heterogeneous uptake by the cancer cells.Choice of excipients such as targeting ligand and PEG may be inappropriate due to lacking overexpressed cancer receptor or availability of excessive metabolizing enzyme and immunoglobulin that defies the survival and action of these excipients rendering nanocarrier fails to reach the target site.Cancer omics analysis should be implied to select excipients which meet the pathophysiological needs,and chitosan nanocarrier with a“transformative physicochemical behavior”is essential to succeed CRISPR-Cas9 delivery.
