Development and Therapeutic Applications of Precise Gene Editing Technology
10.16476/j.pibb.2024.0311
- VernacularTitle:精准基因编辑技术的发展及治疗应用
- Author:
Yi-Meng ZHANG
1
;
Xiao YANG
1
;
Jian WANG
1
;
Zhen-Hua LI
1
Author Information
1. National Center for Protein Sciences (Beijing), Academy of Military Medical Sciences, Beijing 100850, China
- Publication Type:Journal Article
- Keywords:
precise gene editing;
CRISPR/Cas system;
base editing;
prime editing;
gene therapy
- From:
Progress in Biochemistry and Biophysics
2024;51(10):2637-2647
- CountryChina
- Language:English
-
Abstract:
The advent of gene editing represents one of the most transformative breakthroughs in life science, making genome manipulation more accessible than ever before. While traditional CRISPR/Cas-based gene editing, which involves double-strand DNA breaks (DSBs), excels at gene disruption, it is less effective for accurate gene modification. The limitation arises because DSBs are primarily repaired via non-homologous end joining (NHEJ), which tends to introduce indels at the break site. While homology-directed repair (HDR) can achieve precise editing when a donor DNA template is provided, the reliance on DSBs often results in unintended genome damage. HDR is restricted to specific cell cycle phases, limiting its application. Currently, gene editing has evolved to unprecedented levels of precision without relying on DSB and HDR. The development of innovative systems, such as base editing, prime editing, and CRISPR-associated transposases (CASTs), now allow for precise editing ranging from single nucleotides to large DNA fragments. Base editors (BEs) enable the direct conversion of one nucleotide to another, and prime editors (PEs) further expand gene editing capabilities by allowing for the insertion, deletion, or alteration of small DNA fragments. The CAST system, a recent innovation, allows for the precise insertion of large DNA fragments at specific genomic locations. In recent years, the optimization of these precise gene editing tools has led to significant improvements in editing efficiency, specificity, and versatility, with advancements such as the creation of base editors for nucleotide transversions, enhanced prime editing systems for more efficient and precise modifications, and refined CAST systems for targeted large DNA insertions, expanding the range of applications for these tools. Concurrently, these advances are complemented by significant improvements in in vivo delivery methods, which have paved the way for therapeutic application of precise gene editing tools. Effective delivery systems are critical for the success of gene therapies, and recent developments in both viral and non-viral vectors have improved the efficiency and safety of gene editing. For instance, adeno-associated viruses (AAVs) are widely used due to their high transfection efficiency and low immunogenicity, though challenges such as limited cargo capacity and potential for immune responses remain. Non-viral delivery systems, including lipid nanoparticles (LNPs), offer an alternative with lower immunogenicity and higher payload capacity, although their transfection efficiency can be lower. The therapeutic potential of these precise gene editing technologies is vast, particularly in treating genetic disorders. Preclinical studies have demonstrated the effectiveness of base editing in correcting genetic mutations responsible for diseases such as cardiomyopathy, liver disease, and hereditary hearing loss. These technologies promise to treat symptoms and potentially cure the underlying genetic causes of these conditions. Meanwhile, challenges remain, such as optimizing the safety and specificity of gene editing tools, improving delivery systems, and overcoming off-target effects, all of which are critical for their successful application in clinical settings. In summary, the continuous evolution of precise gene editing technologies, combined with advancements in delivery systems, is driving the field toward new therapeutic applications that can potentially transform the treatment of genetic disorders by targeting their root causes.
