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Developing benzylisoquinoline alkaloid-enriched opium poppy via CRISPR-directed genome editing: A review.
Among plant-derived secondary metabolites are benzylisoquinoline alkaloids (BIAs) that play a vital role in medicine. The most conspicuous BIAs frequently found in opium poppy are morphine, codeine, thebaine, papaverine, sanguinarine, and noscapine. BIAs have provided abundant clinically useful drugs used in the treatment of various diseases and ailments With an increasing demand for these herbal remedies, genetic improvement of poppy plants appears to be essential to live up to the expectations of the pharmaceutical industry. With the advent of clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated9 (Cas9), the field of metabolic engineering has undergone a paradigm shift in its approach due to its appealing attributes, such as the transgene-free editing capability, precision, selectivity, robustness, and versatility. The potentiality of the CRISPR system for manipulating metabolic pathways in opium poppy was demonstrated, but further investigations regarding the use of CRISPR in BIA pathway engineering should be undertaken to develop opium poppy into a bioreactor synthesizing BIAs at the industrial-scale levels. In this regard, the recruitment of RNA-guided genome editing for knocking out miRNAs, flower responsible genes, genes involved in competitive pathways, and base editing are described. The approaches presented here have never been suggested or applied in opium poppy so far.
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Next stop for the CRISPR revolution: RNA-guided epigenetic regulators.
Clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) proteins offer a breakthrough platform for cheap, programmable, and effective sequence-specific DNA targeting. The CRISPR-Cas system is naturally equipped for targeted DNA cutting through its native nuclease activity. As such, groups researching a broad spectrum of biological organisms have quickly adopted the technology with groundbreaking applications to genomic sequence editing in over 20 different species. However, the biological code of life is not only encoded in genetics but also in epigenetics as well. While genetic sequence editing is a powerful ability, we must also be able to edit and regulate transcriptional and epigenetic code. Taking inspiration from work on earlier sequence-specific targeting technologies such as zinc fingers (ZFs) and transcription activator-like effectors (TALEs), researchers quickly expanded the CRISPR-Cas toolbox to include transcriptional activation, repression, and epigenetic modification. In this review, we highlight advances that extend the CRISPR-Cas toolkit for transcriptional and epigenetic regulation, as well as best practice guidelines for these tools, and a perspective on future applications.
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Clustered regularly interspaced short palindromic repeats‑associated protein 9 (CRISPR-Cas9) based genome editing in avian primordial germ cells: Comparative technologies, translational applications, and regulatory challenges.
Primordial germ cells (PGCs) are a unique platform for heritable gene editing in avian species, because they allow easy isolation, culture, and can then be reintroduced into the host. CRISPR/Cas9 technologies have advanced avian genome editing by enabling targeted editing of genes and traits for production, health, reproduction, and welfare. This review critically evaluates genome-editing tools in avian PGCs, including CRISPR/Cas9, transcription activator-like effector nucleases (TALENs), base editing, and prime editing. Germline transmission efficiency, suitability, precision, and heritability are compared. Efficiency, cytotoxicity, and translational feasibility of delivery strategies, including viral vectors, electroporation and the use of ribonucleoproteins are assessed. Applications of these techniques in chickens are for muscle growth via myostatin (MSTN) gene disruption, viral resistance via editing of the sodium/hydrogen exchanger 1 (NHE1) gene, and control of male and female ratios through modification of sex determination genes. Additionally, applications in biopharmaceutical protein production and animal biodiversity conservation are also explored. Despite advances, some limitations remain, including low efficiency of homology-directed repair, off-target effects, mosaicism, and variability in transmission through the germ line. Current evidence demonstrates a significant lack of germline validation and scalability creating barriers to translate this potential into commercial avian production, especially, poultry breeding. Regulatory frameworks and their implications for food and commercialization are also discussed. Future research should prioritize precision editing, scalable delivery systems, and regulatory alignment to enable practical, ethical, and responsible implementation.
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Inhibition of hepatitis B virus by the CRISPR/Cas9 system via targeting the conserved regions of the viral genome.
Hepatitis B virus (HBV) remains a global health threat as chronic HBV infection may lead to liver cirrhosis or cancer. Current antiviral therapies with nucleoside analogues can inhibit the replication of HBV, but do not disrupt the already existing HBV covalently closed circular DNA. The newly developed CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated 9) system is a powerful tool to target cellular genome DNA for gene editing. In order to investigate the possibility of using the CRISPR/Cas9 system to disrupt the HBV DNA templates, we designed eight guide RNAs (gRNAs) that targeted the conserved regions of different HBV genotypes, which could significantly inhibit HBV replication both in vitro and in vivo. Moreover, the HBV-specific gRNA/Cas9 system could inhibit the replication of HBV of different genotypes in cells, and the viral DNA was significantly reduced by a single gRNA/Cas9 system and cleared by a combination of different gRNA/Cas9 systems.
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CRISPR-Cas Gene Editing to Cure Serious Diseases: Treat the Patient, Not the Germ Line.
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CRISPR-Cas System-Mediated Genetic Modification in Bacillus spp.: Current Status and Future.
Bacillus spp. are a group of Gram-positive bacteria that have shown significant potential for development in recent years. It is capable of utilizing low-cost substrates to produce various high-value-added compounds, making it widely applicable in fields such as feed, pharmaceuticals, and food. The clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) system-mediated genetic modification is recognized as one of the most efficient technologies. The application of this technology for the genetic improvement of Bacillus spp. greatly enhanced the production performance of these strains. In this review, we summarize the various CRISPR-Cas systems that have been applied to Bacillus spp., with a particular focus on systematically outlining the strategies for implementing CRISPR-Cas-mediated genetic modification in these bacteria. Notably, homologous recombination is the most widely used strategy, while base editing is emerging as a novel and precise approach. Additionally, we discuss the importance of expression regulation strategies in establishing Bacillus spp. as a cell factory. Finally, we propose potential solutions to current technical challenges, providing insights for the development of high-performance genetically modified Bacillus spp. production strains.
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A Review of CRISPR-Based Genome Editing: Survival, Evolution and Challenges.
Precise nucleic acid editing technologies have facilitated the research of cellular function and the development of novel therapeutics, especially the current programmable nucleases-based editing tools, such as the prokaryotic clustered regularly interspaced short palindromic repeats (CRISPR)-associated nucleases (Cas). As CRISPR-based therapies are advancing toward human clinical trials, it is important to understand how natural genetic variation in the human population may affect the results of these trials and even patient safety. The development of "base-editing" technique allows the direct, stable transformation of target DNA base into an alternative in a programmable way, without DNA double strand cleavage or a donor template. Genome-editing techniques hold promises for the treatment of genetic disease at the DNA level by blocking the sequences associated with disease from producing disease-causing proteins. Currently, scientists can select the gene they want to modify, use the Cas9 as a "molecular cutter" to cut it out, and transform it into a more desirable version. In this review, we focus on the recent advances of CRISPR/Cas system by outlining the evolutionary and biotechnological implications of current strategies for improving the specificity and accuracy of these genome-editing technologies.
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Somatic base editing to model oncogenic drivers in breast cancer.
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Genome Editing and Fatty Liver.
Fatty liver disease is characterized as nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). Fatty liver disease is one of the most common causes of chronic liver disease worldwide among adults and children. It is characterized by excessive fat accumulation in the liver cells. It has a genetically heterogenous background with complex pathogenesis and progressions and is accompanied by significant morbidity, mortality, and healthcare costs. NAFLD's risk factors include metabolic syndrome, abdominal obesity, type 2 diabetes, and atherogenic dyslipidemia. ALD is associated with the excessive consumption of alcohol. Here, we describe the functions of various proteins encoded by gene variants contributing to the pathogenesis of nonalcoholic fatty liver disease and alcoholic fatty liver disease. Advancements in genome engineering technology have generated various in vivo and in vitro fatty liver disease models reflecting the genetic abnormalities contributing toward fatty liver disease. We will discuss currently developed different ALD and NAFLD models using the clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) genome editing tool.Furthermore, we will also discuss the salient features of CRISPR/Cas9 editing technology and Cas9 variants such as prime and base editors to replicate genetic topographies linked specifically to ALD and NAFLD. The advantages and limitations of currently available genome delivery methods necessary for optimal gene editing will also be discussed in this review. This review will provide the essential guidance for appropriate genome editing tool selection and proper gene delivery approaches for the effective development of ALD and NAFLD models, leading to the development of clinical therapeutics for fatty liver disease.
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CRISPR-based therapeutics: current challenges and future applications.
The discovery, only a decade ago, of the genome editing power of clustered regularly interspaced short palindromic repeats (CRISPR)-associated nucleases is already reinventing the therapeutic process, from how new drugs are discovered to novel ways to treat diseases. CRISPR-based screens can aid therapeutic development by quickly identifying a drug's mechanism of action and escape mutants. Additionally, CRISPR-Cas has advanced emerging ex vivo therapeutics, such as cell replacement therapies. However, Cas9 is limited as an in vivo therapeutic due to ineffective delivery, unwanted immune responses, off-target effects, unpredictable repair outcomes, and cellular stress. To address these limitations, controls that inhibit or degrade Cas9, biomolecule-Cas9 conjugates, and base editors have been developed. Herein, we discuss CRISPR-Cas systems that advance both conventional and emerging therapeutics.
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