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The Yearbook.
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CRISPR-Cas9: A Potent Gene-editing Tool for the Treatment of Cancer.
The prokaryotic adaptive immune system has clustered regularly interspaced short palindromic repeat. CRISPR-associated protein (CRISPR-Cas) genome editing systems have been harnessed. A robust programmed technique for efficient and accurate genome editing and gene targeting has been developed. Engineered cell therapy, in vivo gene therapy, animal modeling, and cancer diagnosis and treatment are all possible applications of this ground-breaking approach. Multiple genetic and epigenetic changes in cancer cells induce malignant cell growth and provide chemoresistance. The capacity to repair or ablate such mutations has enormous potential in the fight against cancer. The CRISPR-Cas9 genome editing method has recently become popular in cancer treatment research due to its excellent efficiency and accuracy. The preceding study has shown therapeutic potential in expanding our anticancer treatments by using CRISPR-Cas9 to directly target cancer cell genomic DNA in cellular and animal cancer models. In addition, CRISPR-Cas9 can combat oncogenic infections and test anticancer medicines. It may design immune cells and oncolytic viruses for cancer immunotherapeutic applications. In this review, these preclinical CRISPRCas9- based cancer therapeutic techniques are summarised, along with the hurdles and advancements in converting therapeutic CRISPR-Cas9 into clinical use. It will increase their applicability in cancer research.
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Engineering traits through CRISPR/cas genome editing in woody species to improve forest diversity and yield.
Dangers confronting forest ecosystems are many and the strength of these biological systems is deteriorating, thus substantially affecting tree physiology, phenology, and growth. The establishment of genetically engineered trees into degraded woodlands, which would be adaptive to changing climate, could help in subsiding ecological threats and bring new prospects. This should not be resisted due to the apprehension of transgene dispersal in forests. Consequently, it is important to have a deep insight into the genetic structure and phenotypic limits of the reproductive capability of tree stands/population(s) to endure tolerance and survival. Importantly, for a better understanding of genes and their functional mechanisms, gene editing (GeEd) technology is an excellent molecular tool to unravel adaptation progressions. Therefore, GeEd could be harnessed for resolving the allelic interactions for the creation of gene diversity, and transgene dispersal may be alleviated among the population or species in different bioclimatic zones around the globe. This review highlights the potential of the CRISPR/Cas tools in genomic, transcriptomic, and epigenomic-based assorted and programmable alterations of genes in trees that might be able to fix the trait-specific gene function. Also, we have discussed the application of diverse forms of GeEd to genetically improve several traits, such as wood density, phytochemical constituents, biotic and abiotic stress tolerance, and photosynthetic efficiency in trees. We believe that the technology encourages fundamental research in the forestry sector besides addressing key aspects, which might fasten tree breeding and germplasm improvement programs worldwide.
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Transposition of transposable element IS1 in Edwardsiella piscicida mutant generated by CRISPR/Cas9 along with λ-Red recombineering system.
This study aimed to investigate unintended mutations introduced by the CRISPR/Cas9 genome editing system in Edwardsiella piscicida. Whole-genome sequencing was conducted on the wild-type E. piscicida NH1 and its alanine racemase knockout mutants (E. piscicida Δalr325 NH1 and E. piscicida Δalr50 NH1) generated using CRISPR/Cas9 with a λ-Red recombineering system. Comparative genomic analyses revealed that the insertion sequence 1 (IS1) transpositions occurred in the CRISPR/Cas9-edited mutants, disrupting the type I restriction-modification system subunit M gene, in addition to the targeted gene deletion. Interestingly, no IS1 transpositions were detected in mutants produced via conventional plasmid-based allelic exchange, indicating the potential link between CRISPR/Cas9-mediated editing and transposition events. These results suggest that genome editing via CRISPR/Cas9 could trigger IS1 transposition, potentially due to double-stranded DNA breaks. The lack of sequence similarity between the single guide RNA (sgRNA) and the transposed regions suggests that transpositions are not CRISPR/Cas9 off-target effects. This study provides evidence of interactions between mobile genetic elements and genome editing systems, requiring further investigation into their underlying mechanisms.
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CRISPR/Cas9 with single guide RNA expression driven by small tRNA promoters showed reduced editing efficiency compared to a U6 promoter.
Multiplex genome engineering in vivo with CRISPR/Cas9 shows great promise as a potential therapeutic approach. The ability to incorporate multiple single guide RNA (sgRNA) cassettes together with Cas9 gene expression in one AAV vector could greatly enhance the efficiency. In a recent Method article, Mefferd and coworkers indicated that small tRNA promoters could be used to drive sgRNA expression to facilitate the construction of a more effective AAV vector. In contrast, we found that when targeting endogenous genomic loci, CRISPR/Cas9 with tRNA promoter-driven sgRNA expression showed much reduced genome editing activity, compared with significant cleavage with U6 promoter-driven sgRNA expression. Though the underlying mechanisms are still under investigation, our study suggests that the CRISPR/Cas9 system with tRNA promoter-driven sgRNA expression needs to be reevaluated before it can be used for therapeutic genome editing.
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Brain-targeted CRISPR/Cas9 nanomedicine for effective glioblastoma therapy.
CRISPR/Cas9 gene-editing technology shows great potential for treating a variety of diseases, such as glioblastoma multiforme (GBM). However, CRISPR components suffer from inherent delivery challenges, such as poor in vivo stability of Cas9 protein and gRNA, low blood-brain barrier (BBB) permeability and non-specific tissue or cell targeting. These defects have limited the application of Cas9/gRNA ribonucleoprotein (RNP) complexes for GBM therapy. Here, we developed a brain-targeted CRISPR/Cas9 based nanomedicine by fabricating an angiopep-2 decorated, guanidinium and fluorine functionalized polymeric nanoparticle with loading Cas9/gRNA RNP for the treatment of GBM. The guanidinium and fluorine domains of our polymeric nanoparticles were both capable of interacting with Cas9/gRNA RNP to stabilize it in blood circulation, without impairing its activity. Moreover, by leveraging angiopep-2 peptide functionality, the RNP nanoparticles efficiently crossed the BBB and accumulated in brain tumors. In U87MG cells, we achieved approximately 32% gene knockout and 67% protein reduction in the targeted proto-oncogene polo-like kinase 1 (PLK1). This was sufficient to suppress tumor growth and significantly improved the median survival time of mice bearing orthotopic glioblastoma to 40 days, while inducing negligible side or off-target effects. These results suggest that the developed brain-targeted CRISPR/Cas9 based nanomedicine shows promise for effective human glioblastoma gene therapy.
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Genome editing outside of controlled facilities: A review of plausible futures and risks.
Vectors for delivering proteins and/or nucleic acids into the cells of whole organisms, from single to multicellular, are rapidly advancing. Common cargos are nucleic acids needed to express the components of a genome editing reaction, or ribonucleoproteins (RNP) that can act immediately upon delivery. In only 20 years, improvements in associated formulation technologies have decreased the dependence of genome editing on the need for a laboratory or trained personnel, allowing for genome editing outside of controlled facilities. As this happens, both target and non-target organisms may be exposed to active biological agents, necessitating a new framework for risk assessment. Some scientists deny developments for gene editing in uncontrolled environments, leading to scientifically unjustified dismissals of risk.
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Gene Knockout of Beneficial Plant-associated Bacillus spp. Using the CRISPR-Cas9 Double Plasmid System.
Bacillus spp. have great agricultural potential as a plant growth promoter and biocontrol agent. However, little is known concerning the bacterial molecular basis for the improvement of plant fitness. Thus, it is highly desirable to develop techniques that can contribute to the elucidation of the genetic basis for the mechanisms involved in beneficial bacterium-plant interactions. In this context, CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 is a powerful tool based on programmable molecular scissors that perform precise incisions in any DNA sequence. CRISPR-Cas9 can alter gene sequences and constitutes a cutting-edge tool to elucidate the role and function of bacterial genes associated with the benefits of plant interactions. The method described here uses a feasible CRISPR-Cas9 system in a double plasmid, one plasmid harboring the Cas9 endonuclease and the other the sgRNA, to promote gene knockout/editing in the Bacillus genus. This approach favors high efficiency in generating mutants for one or more genes in continuous or multiplex editing. Additionally, due to its universality, it can be applied to genera other than Bacillus.
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Breaking the Rules.
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Precision genome editing in plants using gene targeting and prime editing: existing and emerging strategies.
Precise modification of plant genomes, such as seamless insertion, deletion, or replacement of DNA sequences at a predefined site, is a challenging task. Gene targeting (GT) and prime editing are currently the best approaches for this purpose. However, these techniques are inefficient in plants, which limits their applications for crop breeding programs. Recently, substantial developments have been made to improve the efficiency of these techniques in plants. Several strategies, such as RNA donor templating, chemically modified donor DNA template, and tandem-repeat homology-directed repair, are aimed at improving GT. Additionally, improved prime editing gRNA design, use of engineered reverse transcriptase enzymes, and splitting prime editing components have improved the efficacy of prime editing in plants. These emerging strategies and existing technologies are reviewed along with various perspectives on their future improvement and the development of robust precision genome editing technologies for plants.
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