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CRISPR-Cas9 Genome Editing for Treatment of Atherogenic Dyslipidemia.
Although human genetics has resulted in the identification of novel lipid-related genes that can be targeted for the prevention of atherosclerotic vascular disease, medications targeting these genes or their protein products have short-term effects and require frequent administration during the course of the lifetime for maximal benefit. Genome-editing technologies, such as CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR-associated 9) have the potential to permanently alter genes in the body and produce long-term and even lifelong protection against atherosclerosis. In this review, we discuss recent advances in genome-editing technologies and early proof-of-concept studies of somatic in vivo genome editing in mice that highlight the potential of genome editing to target disease-related genes in patients, which would establish a novel therapeutic paradigm for atherosclerosis.
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Tracking CRISPR's Footprints.
The programmable clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) and CRISPR-Cas9-derived gene editing and manipulation tools have revolutionized biomedical research over the past few years. One important category of assisting technologies in CRISPR gene editing is methods used for detecting and quantifying indels (deletions or insertions). These indels are caused by the repair of CRISPR-Cas9-introduced DNA double-stranded breaks (DBSs), known as CRISPR's DNA cleavage footprints. In addition, CRISPR-Cas9 can also leave footprints to the DNA without introducing DSBs, known as CRISPR's DNA-binding footprints. The indel tracking methods have contributed greatly to the improvement of CRISPR-Cas9 activity and specificity. Here, we review and discuss strategies developed over that past few years to track the CRISPR's footprints, their advantages, and limitations.
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Highly efficient CRISPR-mediated base editing for the gut Bacteroides spp. with pnCasBS-CBE.
Bacteroidales are the most abundant order of bacteria in the healthy human gut and have the potential as a therapeutic agent. We constructed a pnCasBS-CBE system for base editing in the Bacteroides thetaiotaomicron to expand their genetic toolkit, which is able to efficiently convert a C:G to a T:A in the genome. As a functional proof-of-concept, we used the pnCasBS-CBE system to successfully introduce nonsynonymous mutation and stop codons to the genes involved in carbohydrate metabolism. The system also allowed for multiplexed gene editing with a single plasmid, enabling efficient editing of up to four genes in a single experiment. Furthermore, the pnCasBS-CBE editing system was validated and successfully applied in four other non-model gut Bacteroides species for genome editing. An unbiased genome-wide SNPs analysis indicated that the pnCasBS-CBE system showed high fidelity and applicability. Thus, this study provides a powerful clustered regularly interspaced short palindromic repeats (CRISPR)-mediated genome editing toolbox for functional genomic analysis in Bacteroidales.
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CRISPR for cystic fibrosis: Advances and insights from a systematic review.
Cystic fibrosis (CF) is a severe genetic disorder caused by loss-of-function mutations in the CFTR gene. Gene-editing approaches have the potential to correct such mutations. This systematic review outlines the mechanisms of the main CRISPR-based technologies, and, through cross-study comparisons, analyzes 27 research articles that applied them to target CF-causing variants. We report and discuss the strategy design, target cell selection, editing efficiency, prevalence of editing byproducts, and levels of CFTR functional restoration achieved in each work, with the aim of providing technical insights for further exploration of CRISPR-based gene-editing approaches. Our findings show that the F508del and W1282X mutations were the most extensively studied CF-causing variants, though over fifteen mutations were targeted overall. The majority of works under review explored the use of homology-directed repair or base editing, with a growing number of studies reporting efficient prime editing. Some studies tackled multiple individual mutations, compared different editors, or tested strategies across various models, while others focused on approaches that rescue CFTR function without directly correcting a mutation. Several works also proposed strategies that could address multiple variants with a single approach, while others highlighted technical difficulties in editing certain regions of the CFTR gene. This cross-study comparison also emphasizes the need for standardized reporting of editing efficiency and functional recovery, and stresses the importance of further single-cell RNA sequencing and in vivo studies to reach clinically relevant conclusions. As gene-editing techniques continue to evolve, and with over 60 ongoing CRISPR-based clinical trials, there is growing optimism for meaningful advancements in CF gene-editing therapeutics.
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CRISPR-guided base editor enables efficient and multiplex genome editing in bacterial cellulose-producing Komagataeibacter species.
UNLABELLED: Bacterial cellulose (BC) is an extracellular polysaccharide produced by bacteria that has wide applications in the food industry, tissue engineering, and battery manufacturing. Genome editing of BC-producing Komagataeibacter species is expected to optimize BC production and its properties. However, the available technology can target only one gene at a time and requires foreign DNA templates, which may present a regulatory hurdle for genetically modified organisms. In this study, we developed a clustered regularly interspaced short palindromic repeats (CRISPR)-guided base editing method for Komagataeibacter species using Cas9 nickase and cytidine deaminase. Without foreign DNA templates, C-to-T conversions were performed within an 8 bp editing window with 90% efficiency. Double- and triple-gene editing was achieved with 80%-90% efficiency. Fusing uracil-DNA glycosylase with the base editor enabled C-to-G editing. The base editor worked efficiently with various Komagataeibacter species. Finally, mannitol metabolic genes were investigated using base-editing-mediated gene inactivation. This study provides a powerful tool for multiplex genome editing of Komagataeibacter species. IMPORTANCE: Komagataeibacter, a bacterial genus belonging to the family Acetobacteraceae, has important applications in food and material biosynthesis. However, the genome editing of Komagataeibacter relies on traditional homologous recombination methods. Therefore, only one gene can be manipulated in each round using foreign DNA templates, which may present a regulatory hurdle for genetically modified organisms when microorganisms are used in the food industry. In this study, a powerful base editing technology was developed for Komagataeibacter species. C-to-T and C-to-G base conversions were efficiently implemented at up to three loci in the Komagataeibacter genome. This base editing system is expected to accelerate basic and applied research on Komagataeibacter species.
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Toward CRISPR Therapies for Cardiomyopathies.
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Editorial: Genome Editing Goes Beyond CRISPR with the Emergence of 'Bridge' RNA Editing.
Therapeutic human gene editing technologies continue to advance, with the endonuclease, clustered regularly interspaced short palindromic repeats (CRISPR) being one of the most rapidly developing technologies. Recently, in 2024, a method of RNA editing called 'bridge editing' has been described in bacteria, which is more powerful and has broader applications than CRISPR to reshape the genome. The term 'bridge editing' is used because the method physically links, or bridges, two sections of DNA and can alter large sections of a genome. 'Bridge editing' relies on insertion sequence (IS) elements, the simplest autonomous transposable elements in prokaryotic genomes. This method provides a unified mechanism for the three fundamental types of DNA rearrangement required for genome design: inversion, insertion, and excision. The 'bridge' recombination system could expand the range and diversity of nucleic acid-guided therapeutic systems beyond RNA interference and CRISPR. This editorial aims to introduce new developments in 'bridge' RNA editing that have the increased potential to reshape the genome.
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Critical cancer vulnerabilities identified by unbiased CRISPR/Cas9 screens inform on efficient cancer Immunotherapy.
The mutational landscape of human cancers is highly complex. While next generation sequencing aims to comprehensively catalogue somatic alterations in tumor cells, it fails to delineate driver from passenger mutations. Functional genomic approaches, particularly CRISPR/Cas9, enable both gene discovery, and annotation of gene function. Indeed, recent CRISPR/Cas9 technologies have flourished with the development of more sophisticated and versatile platforms capable of gene knockouts to high throughput genome wide editing of a single nucleotide base. With new platforms constantly emerging, it can be challenging to navigate what CRISPR tools are available and how they can be effectively applied to understand cancer biology. This review provides an overview of current and emerging CRISPR technologies and their power to model cancer and identify novel treatments. Specifically, how CRISPR screening approaches have been exploited to enhance immunotherapies through the identification of tumor intrinsic and extrinsic mechanisms to escape immune recognition will be discussed.
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Development and application of CRISPR/Cas9 technologies in genomic editing.
Genomic editing to correct disease-causing mutations is a promising approach for the treatment of human diseases. As a simple and programmable nuclease-based genomic editing tool, the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system has substantially improved the ability to make precise changes in the human genome. Rapid development of CRISPR-based technologies in recent years has expanded its application scope and promoted CRISPR-based therapies in preclinical trails. Here, we review the application of the CRISPR system over the last 2 years; including its development and application in base editing, transcription modulation and epigenetic editing, genomic-scale screening, and cell and embryo therapy. Finally, the prospects and challenges related to application of CRISPR/Cas9 technologies are discussed.
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CRISPR-mediated RNA base editing: a promising strategy to rescue deafness.
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