a Department of Molecular Medicine , University of Padova , Padova , Italy.
Expert Rev Anti Infect Ther. 2017 Nov;15(11):1001-1013. doi: 10.1080/14787210.2017.1400379. Epub 2017 Nov 8.
Genome editing by programmable nucleases represents a promising tool that could be exploited to develop new therapeutic strategies to fight infectious diseases. These nucleases, such as zinc-finger nucleases, transcription activator-like effector nucleases, clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated protein 9 (Cas9) and homing endonucleases, are molecular scissors that can be targeted at predetermined loci in order to modify the genome sequence of an organism. Areas covered: By perturbing genomic DNA at predetermined loci, programmable nucleases can be used as antiviral and antimicrobial treatment. This approach includes targeting of essential viral genes or viral sequences able, once mutated, to inhibit viral replication; repurposing of CRISPR-Cas9 system for lethal self-targeting of bacteria; targeting antibiotic-resistance and virulence genes in bacteria, fungi, and parasites; engineering arthropod vectors to prevent vector-borne infections. Expert commentary: While progress has been done in demonstrating the feasibility of using genome editing as antimicrobial strategy, there are still many hurdles to overcome, such as the risk of off-target mutations, the raising of escape mutants, and the inefficiency of delivery methods, before translating results from preclinical studies into clinical applications.
基因组编辑由可编程核酸酶代表了一种很有前途的工具,可以用来开发新的治疗策略来对抗传染病。这些核酸酶,如锌指核酸酶、转录激活样效应物核酸酶、成簇规律间隔短回文重复(CRISPR)-CRISPR 相关蛋白 9(Cas9)和归巢内切酶,是分子剪刀,可以靶向预定的基因座,以修饰生物体的基因组序列。涵盖领域:通过在预定的基因座上扰动基因组 DNA,可编程核酸酶可用作抗病毒和抗菌治疗。这种方法包括靶向必需的病毒基因或能够突变以抑制病毒复制的病毒序列;重新利用 CRISPR-Cas9 系统对细菌进行致命的自我靶向;靶向细菌、真菌和寄生虫中的抗生素耐药性和毒力基因;设计节肢动物载体以预防媒介传播的感染。专家评论:虽然在证明将基因组编辑作为抗菌策略的可行性方面已经取得了进展,但在将临床前研究的结果转化为临床应用之前,仍有许多障碍需要克服,例如脱靶突变的风险、逃逸突变体的产生以及递送方法的效率低下。