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Gene editing in liver diseases.
The deliberate and precise modification of the host genome using engineered nucleases represents a groundbreaking advancement in modern medicine. Several clinical trials employing these approaches to address metabolic liver disorders have been initiated, with recent remarkable outcomes observed in patients with transthyretin amyloidosis, highlighting the potential of these therapies. Recent technological improvements, particularly CRISPR Cas9-based technology, have revolutionized gene editing, enabling in vivo modification of the cellular genome for therapeutic purposes. These modifications include gene supplementation, correction, or silencing, offering a wide range of therapeutic possibilities. Moving forward, we anticipate witnessing the unfolding therapeutic potential of these strategies in the coming years. The aim of our review is to summarize preclinical data on gene editing in animal models of inherited liver diseases and the clinical data obtained thus far, emphasizing both therapeutic efficacy and potential limitations of these medical interventions.
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The dCas9-SSAP as a promising genome editing tool in malaria parasites.
Measures to combat the Plasmodium parasites which cause malaria have become compromised because of reliance on a small arsenal of drugs, emerging drug resistance and the lack of effective vaccines. A promising avenue for addressing these challenges is the revolutionary gene-editing technology CRISPR-Cas9, due to its high efficiency and ease of design for genetic manipulation. The catalytically inactive Cas9 (dCas9)-microbial single-stranded annealing proteins (SSAP)(dCas9-SSAP) is a recently emerged next-generation gene editing system added to the ever-growing CRISPR-Cas9-based technologies. While the classical Cas9-nuclease technologies are "double-strand break, damage-repair systems", the dCas9-SSAP is distinctively a "cleavage-free" editing tool. Unlimited to the Plasmodium genome, Cas9-nucleases imprint inheritable genetic scars on the subject genomes when applied. Here, we discussed the DSB genotoxicity pitfalls of existing nuclease-based editing tools, especially CRISPR-Cas9, and how the dCas9-SSAP presents a formidable option to the drawbacks within the context of Plasmodium genome editing. Then, we sought to infer a plausible mechanistic framework that could account for dCas9-SSAP-mediated genome editing. Finally, we discussed how dCas9-SSAP aligns with Plasmodium parasites' biology. This review would set the stage for continued research into the potential of this new, exciting technology in malaria parasites.
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Hypoxia-Responsive Gene Editing to Reduce Tumor Thermal Tolerance for Mild-Photothermal Therapy.
Near-infrared (NIR)-light-triggered photothermal therapy (PTT) is usually associated with undesirable damage to healthy organs nearby due to the high temperatures (>50 °C) available for tumor ablation. Low-temperature PTT would therefore have tremendous value for clinical application. Here, we construct a hypoxia-responsive gold nanorods (AuNRs)-based nanocomposite of CRISPR-Cas9 for mild-photothermal therapy via tumor-targeted gene editing. AuNRs are modified with azobenzene-4,4'-dicarboxylic acid (p-AZO) to achieve on-demand release of CRISPR-Cas9 using hypoxia-responsive azo bonds. In the hypoxic tumor microenvironment, the azo groups of the hypoxia-activated CRISPR-Cas9 nanosystem based on gold nanorods (APACPs) are selectively reduced by the overexpression of reductases, leading to the release of Cas9 and subsequent gene editing. Owing to the knockout of HSP90α for reducing the thermal resistance of cancer cells, highly effective tumor ablation both in vitro and in vivo was achieved with APACPs under mild PTT.
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A scoping review of gene editing in clinical trials: identifying aspects of trial design to accelerate clinical adoption.
BACKGROUND: Initial clinical trials of gene editing have recently emerged and generated significant interest in this promising therapy. A scoping review is needed to understand aspects of study design that may accelerate further clinical translation. METHODS: A systematic search of published clinical trials was conducted to May 22, 2025. RESULTS: Twenty-nine published trials were identified for analysis (420 patients; median ages 6 months to 90 years). The most common gene editing technology used was CRISPR-Cas9 (23 studies, 79%). Hematopoietic cells were targeted most frequently, and leukemias and lymphomas were the most common clinical indications (8 studies; 27.5%), followed by hemoglobin disorders (6; 20.6%), solid tumors (6; 20.6%), rare genetic diseases (5; 17.2%), and others (4; 13.8%). All trials were early-phase (Phase I/II) with only 1 controlled study (29 patients). Six studies used in vivo approaches while all others performed gene editing ex vivo. Gene transfection was by electroporation (9 studies; 31.0%), viral-mediated transfection (6; 20.7%), or by lipid nanoparticles (3; 10.3%). Commonly reported outcomes included early safety and adverse events, mortality, persistence of edited cells, clinical and functional responses. Studies of leukemia/lymphoma reported rates of complete remission in 15-92% while we identified important and sustained increases in mean hemoglobin levels in studies of hemoglobin disorders. Edited cells were detected in most studies at 3 and 6 months but later timepoints were reported less frequently. While early serious adverse events were infrequently observed, reporting of longer-term outcomes was lacking. CONCLUSION: Gene editing appears feasible and generally safe in humans although important safety outcomes such as long-term oncogenic surveillance outcomes remain to be addressed. A broad range of conditions have been treated, and most often leverages the CRISPR-Cas9 technology with transfection by electroporation. The persistence of edited cells remains ill-defined and longer-term safety outcomes are needed. Studies optimizing CART therapy for leukemia/lymphoma and treatment of hemoglobin disorders appear poised for significant clinical adoption.
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Application of genome editing techniques to regulate gene expression in crops.
BACKGROUND: Enhanced agricultural production is urgently required to meet the food demands of the increasing global population. Abundant genetic diversity is expected to accelerate crop development. In particular, the development of the CRISPR/Cas genome editing technology has greatly enhanced our ability to improve crop's genetic diversity through direct artificial gene modification. However, recent studies have shown that most crop improvement efforts using CRISPR/Cas techniques have mainly focused on the coding regions, and there is a relatively lack of studies on the regulatory regions of gene expression. RESULTS: This review briefly summarizes the development of CRISPR/Cas system in the beginning. Subsequently, the importance of gene regulatory regions in plants is discussed. The review focuses on recent developments and applications of mutations in regulatory regions via CRISPR/Cas techniques in crop breeding. CONCLUSION: Finally, an outline of perspectives for future crop breeding using genome editing technologies is provided. This review provides new research insights for crop improvement using genome editing techniques.
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A pipeline for precise and efficient genome editing by sgRNA-Cas9 RNPs in Drosophila.
Genome editing via homology-directed repair (HDR) has made possible precise and deliberate modifications to gene sequences. CRISPR/Cas9-mediated HDR is the simplest means to carry this out. However, technical challenges remain to improve efficiency and broaden applicability to any genetic background of Drosophila melanogaster as well as to other Drosophila species. To address these issues, we developed a two-stage marker-assisted strategy in which embryos are injected with RNPs and pre-screened using T7EI. Using sgRNA in complex with recombinant Cas9 protein, we assayed each sgRNA for genome-cutting efficiency. We then conducted HDR using sgRNAs that efficiently cut target genes and the application of a transformation marker that generates RNAi against eyes absent. This allows for screening based on eye morphology rather than colour. These new tools can be used to make a single change or a series of allelic substitutions in a region of interest, or to create additional genetic tools such as balancer chromosomes.
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Pharmacogenomics and CRISPR-based therapies.
Pharmacogenomics and CRISPR-based treatments are two areas of precision medicine that are advancing together. Pharmacogenomics involves studying how differences in someone's genes can change the effect of medications on them. Pharmacogenomics helps reduce adverse reactions to drugs and improve healing by choosing and measuring drugs according to a patient's genetic information. Additionally, CRISPR-Cas systems now serve as leading genome editing tools that allow precise alterations at given points of the genome. CRISPR technology's use in pharmacogenomics creates new opportunities for modifying gene expression, fixing harmful mutations, and creating innovative treatment approaches. A more proactive approach to illness treatment is supported by this synergy, in which genetic factors serve as both direct targets for intervention and a basis for medication selection. This chapter examines the theoretical and practical frameworks that link CRISPR-based treatments with pharmacogenomics, emphasizing recent uses in pharmacoresistance, cancer, and monogenic diseases. To guarantee safe and fair deployment, it also covers the ethical, legal, and technical issues that need to be resolved. When combined, these technologies hold the potential to revolutionize medicine by facilitating individualized and curative drugs.
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Genome Editing with CRISPR-Cas9: A Budding Biological Contrivance for Colorectal Carcinoma Research and its Perspective in Molecular Medicine.
Genome editing is an addition, deletion, or replacement of a gene to remove or initiating explicit and preferred characters in the genome. Utilizing gene-editing tools like CRISPR-Cas9 technology could be accomplished either by gene-based methodology or protein-based technology that has been under scrutiny for the protracted time wherein physical techniques, viral and non-viral strategies have been utilized together. Transplanting ex vivo CRISPR edited cells empowers screening of single guide RNAs with high-throughput and CRISPR based screening in organoids transplantation to validate cancer cells including colorectal carcinoma in various phases of its development and treatment.CRISPR knockout screens have recognized genes that drive interest in colon cancer to develop hallmarks, especially in some cancer cell lines with single guide RNA, to disclose drug resistance mechanisms. One advantage of this method is to deal with CRISPR knockout genomic screening, which disrupts gene expression, rather than the partial knockdown that is mostly done with RNA interference and CRISPR/Cas technology. This technique is used to treat different forms of cancer because of its proficient editing of the target gene, along with the CRISPR/Cas system. Latest research has shown that the CRISPR/Cas gene-editing technique has theoretically reformed the expression in colorectal carcinoma of long non-coding RNA. For the next decade CRISPR/Cas9 technology will positively fuel the development of more in vivo gene editing clinical trials in colon cancer and will have an enormous impact on molecular medicine.
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Generation of NPHP1 knockout human pluripotent stem cells by a practical biallelic gene deletion strategy using CRISPR/Cas9 and ssODN.
CRISPR/Cas9 genome editing underwent remarkable progress and significantly contributed to the development of life sciences. Induced pluripotent stem cells (iPSCs) have also made a relevant contribution to regenerative medicine, pharmacological research, and genetic disease analysis. However, knockout iPSC generation with CRISPR/Cas9 in general has been difficult to achieve using approaches such as frameshift mutations to reproduce genetic diseases with full-length or nearly full-length gene deletions. Moreover, splicing and illegitimate translation could make complete knockouts difficult. Full-length gene deletion methods in iPSCs might solve these problems, although no such approach has been reported yet. In this study, we present a practical two-step gene-editing strategy leading to the precise, biallelic, and complete deletion of the full-length NPHP1 gene in iPSCs, which is the first report of biallelic (compound heterozygous) full-gene deletion in iPSCs using CRISPR/Cas9 and single-stranded oligodeoxynucleotides mainly via single-strand template repair (SSTR). Our strategy requires no selection or substances to enhance SSTR and can be used for the analysis of genetic disorders that are difficult to reproduce by conventional knockout methods.
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Harnessing the Native Type I-F CRISPR-Cas System of Acinetobacter baumannii for Genome Editing and Gene Repression.
INTRODUCTION: The rapid emergence of infections caused by multidrug-resistant Acinetobacter baumannii (A. baumannii) has posed a serious threat to global public health. It has therefore become important to obtain a deeper understanding of the mechanisms of multidrug resistance and pathogenesis of A. baumannii; however, there are still relatively few genetic engineering tools for this. Although A. baumannii possesses Type I-F CRISPR-Cas systems, they have not yet been used for genetic modifications. METHODS: A single plasmid-mediated native Type I-F CRISPR-Cas system for gene editing and gene regulation in A. baumannii was developed. The protospacer adjacent motif sequence was identified as 5'-NCC-3' by analysis of the CRISPR array. RESULTS: Through introduction of the RecAb homologous recombination system, the knockout efficiency of the oxyR gene significantly increased from 12.5% to 75.0% in A. baumannii. To investigate transcriptional inhibition by the Type I-F CRISPR system, the gene encoding its Cas2-3 nuclease was deleted and the native Type I-F Cascade effector was repurposed to regulate transcription of alcohol dehydrogenase gene adh4. The level of adh4 transcription was inhibited by up to 900-fold compared with the control. The Cascade transcriptional module was also successfully applied in a clinical Klebsiella pneumoniae isolate. CONCLUSION: This study proposed a tool for future exploration of the genetic characteristics of A. baumannii or other clinical strains.
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