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Single Base Editing Using Cytidine Deaminase to Change Grain Size and Seed Coat Color in Rice.
The fast-moving CRISPR technology has allowed plant scientists to manipulate plant genomes in a targeted manner. So far, most of the applications were focused on gene knocking out by creating indels. However, more precise genome editing tools are demanded to assist the introduction of functional single nucleotide polymorphisms (SNPs) in breeding programs. The CRISPR base editing tools were developed to meet this need. In this chapter, we present a cytidine deaminase base editing method for editing the point mutations that control the grain size and seed coat color in rice.
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Revolutionising healing: Gene Editing's breakthrough against sickle cell disease.
Recent advancements in gene editing illuminate new potential therapeutic approaches for Sickle Cell Disease (SCD), a debilitating monogenic disorder caused by a point mutation in the β-globin gene. Despite the availability of several FDA-approved medications for symptomatic relief, allogeneic hematopoietic stem cell transplantation (HSCT) remains the sole curative option, underscoring a persistent need for novel treatments. This review delves into the growing field of gene editing, particularly the extensive research focused on curing haemoglobinopathies like SCD. We examine the use of techniques such as CRISPR-Cas9 and homology-directed repair, base editing, and prime editing to either correct the pathogenic variant into a non-pathogenic or wild-type one or augment fetal haemoglobin (HbF) production. The article elucidates ways to optimize these tools for efficacious gene editing with minimal off-target effects and offers insights into their effective delivery into cells. Furthermore, we explore clinical trials involving alternative SCD treatment strategies, such as LentiGlobin therapy and autologous HSCT, distilling the current findings. This review consolidates vital information for the clinical translation of gene editing for SCD, providing strategic insights for investigators eager to further the development of gene editing for SCD.
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Reporter Mice for Gene Editing: A Key Tool for Advancing Gene Therapy of Rare Diseases.
Most rare diseases are caused by mutations and can have devastating consequences. Precise gene editing by CRISPR/Cas is an exciting possibility for helping these patients, if no irreversible developmental defects have occurred. To optimize gene editing therapy, reporter mice for gene editing have been generated which, by expression of reporter genes, indicate the efficiency of precise and imprecise gene editing. These mice are important tools for testing and comparing novel gene editing methodologies. This review provides a comprehensive overview of reporter mice for gene editing which all have been used for monitoring CRISPR/Cas-mediated gene editing involving DNA double-strand breaks (DSBs). Furthermore, we discuss how reporter mice can be used for quickly checking genetic alterations by base editing (BE) or prime editing (PE).
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In-vivo CRISPR/Base-Editing "One-Shot" Therapies Targeting PCSK9.
PURPOSE OF REVIEW: To assess and present the current state of gene editing for reduction of atherosclerotic cardiovascular disease (ASCVD) with emphasis on technology and ongoing trials for genetic editing of protein convertase subtilisin/kexin type 9 (PCSK9). RECENT FINDINGS: There are two ongoing clinical trials in humans to edit PCSK9 using CRISPR-Cas9 base editing technology packaged within lipid nanoparticles (LNPs). Preliminary interim and preclinical data suggest that this strategy is effective for long-term reduction of PCSK9 and LDL-C following a single IV infusion. Monoclonal antibodies that neutralize circulating PCSK9 have demonstrated the utility of PCSK9 inhibition for reducing LDL-C and ASCVD. Although there is an increasing number of pharmacologic strategies for inhibiting PCSK9, gene editing is an attractive option due to its potential to permanently reduce circulating PCSK9 levels and by extension LDL-C and ASCVD. There are two ongoing clinical trials in humans investigating the safety and efficacy of gene editing for PCSK9 with encouraging preliminary results. In this review, we will describe the background of PCSK9 as a target, the gene editing machinery and the preliminary results. We also explore the unique safety challenges of this technology and propose considerations for appropriate patient populations to maintain net positive benefits despite unknowns.
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Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer.
Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 editing of immune checkpoint genes could improve the efficacy of T cell therapy, but the first necessary undertaking is to understand the safety and feasibility. Here, we report results from a first-in-human phase I clinical trial of CRISPR-Cas9 PD-1-edited T cells in patients with advanced non-small-cell lung cancer (ClinicalTrials.gov NCT02793856). Primary endpoints were safety and feasibility, and the secondary endpoint was efficacy. The exploratory objectives included tracking of edited T cells. All prespecified endpoints were met. PD-1-edited T cells were manufactured ex vivo by cotransfection using electroporation of Cas9 and single guide RNA plasmids. A total of 22 patients were enrolled; 17 had sufficient edited T cells for infusion, and 12 were able to receive treatment. All treatment-related adverse events were grade 1/2. Edited T cells were detectable in peripheral blood after infusion. The median progression-free survival was 7.7 weeks (95% confidence interval, 6.9 to 8.5 weeks) and median overall survival was 42.6 weeks (95% confidence interval, 10.3-74.9 weeks). The median mutation frequency of off-target events was 0.05% (range, 0-0.25%) at 18 candidate sites by next generation sequencing. We conclude that clinical application of CRISPR-Cas9 gene-edited T cells is generally safe and feasible. Future trials should use superior gene editing approaches to improve therapeutic efficacy.
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CRISPR-Cas9 gene editing approaches in colorectal cancer: Current progress and future prospects.
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, characterized by genetic heterogeneity and the accumulation of mutations in key oncogenes and tumor suppressor genes. CRISPR-Cas9 technology has greatly advanced genetic research by enabling precise genome editing. This review focuses on the innovative applications of CRISPR-Cas9 in CRC research, particularly its role in identifying novel therapeutic targets, elucidating mechanisms of drug resistance, and uncovering metabolic and stem cell pathway alterations in tumorigenesis. We highlight the diverse CRISPR systems, including Cas9, Cas12, Cas13, and advanced variants such as CRISPR activation (CRISPRa), CRISPR interference (CRISPRi), base editing, and prime editing, which have expanded gene knockout studies and enhanced our understanding of CRC. Despite these breakthroughs, challenges such as off-target effects and delivery limitations remain. Ongoing efforts to refine CRISPR technology aim to enhance its precision and clinical applicability, ultimately paving the way for more effective and personalized treatment strategies for CRC. In this review, we explore these advances and focus on the latest developments in CRISPR-based approaches for CRC treatment.
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Prediction of synonymous corrections by the BE-FF computational tool expands the targeting scope of base editing.
Base editing is a genome-editing approach that employs the CRISPR/Cas system to precisely install point mutations within the genome. A deaminase enzyme is fused to a deactivated Cas and enables transition conversions. The diversified repertoire of base editors provides a wide range of base editing possibilities. However, existing base editors cannot induce transversion substitutions and activate only within a specified region relative to the binding site, thus, they cannot precisely correct every point mutation. Here, we present BE-FF (Base Editors Functional Finder), a novel computational tool that identifies suitable base editors to correct the translated sequence erred by a point mutation. When a precise correction is impossible, BE-FF aims to mutate bystander nucleotides in order to induce synonymous corrections that will correct the coding sequence. To measure BE-FF practicality, we analysed a database of human pathogenic point mutations. Out of the transition mutations, 60.9% coding sequences could be corrected. Notably, 19.4% of the feasible corrections were not achieved by precise corrections but only by synonymous corrections. Moreover, 298 cases of transversion-derived pathogenic mutations were detected to be potentially repairable by base editing via synonymous corrections, although base editing is considered impractical for such mutations.
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Base-editing screens illuminate variant effects in human hematopoiesis.
In a recent issue of Cell, Martin-Rufino et al. develop a strategy for performing high-throughput base-editing CRISPR screens coupled with single-cell readouts in the context of human hematopoiesis. Through a series of proof-of-principle experiments, the authors demonstrate the potential of base-editing screens for the study and treatment of hematological disorders.
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The Application of Base-Editing Technology to Investigate Virus-Host Interactions and Antiviral Therapeutic Strategies.
Understanding viral pathogenesis and developing effective countermeasures hinge on deciphering the complex relationships between viruses and their hosts. While conventional approaches have shown limitations in unraveling these intricate interactions, researchers are now turning to cutting-edge genetic tools, particularly base-editing technology. This section explores how base editing can be innovatively applied to investigate virus-host dynamics and to create novel antiviral therapeutic approaches.
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Expanding the CRISPR base editing toolbox in Drosophila melanogaster.
CRISPR base editors can introduce point mutations into DNA precisely, and cytosine base editors (CBEs) catalyze C to T transitions. While CBEs have been thoroughly explored in cell culture and organisms such as mice, little is known about DNA base editing in insects. In this study, we evaluated germline editing rates of three different CBEs expressed under actin (ubiquitous) or nanos (germline) promoters utilizing Drosophila melanogaster. The original Rattus norvegicus-derived cytosine deaminase APOBEC1 (rAPO-1) displayed high base editing rates (~99%) with undetectable indel formation. Additionally, we show that base editors can be used for generating male sterility and female lethality. Overall, this study highlights the importance of promoter choice and sex-specific transmission for efficient base editing in flies while providing new insights for future genetic biocontrol designs in insects.
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