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CRISPR: History and perspectives to the future.
This review summarizes the information about the history and future of the CRISPR/Cas9 method. Genome editing can be perceived as a group of technologies that allow scientists to change the DNA of an organism. These technologies involve the deletion, insertion, or modification of the genome at a specific site in a DNA sequence. Gene therapy in humans has a perspective to be used to eliminate the gene responsible for a particular genetic disorder. The review focuses on the key elements of this promising method and the possibility of its application in the treatment of cancer and genetic diseases.
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Location, location, location: Use of CRISPR-Cas9 for genome editing in human pathogenic fungi.
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Biogenic materials for CRISPR delivery and therapeutics.
CRISPR, as an emerging gene-editing technology, has been widely used in multidisciplinary fields, including genetic diseases and some cancers. However, it remains a challenge to efficiently deliver CRISPR for safe and efficient genome editing. Currently, biomimetic materials have become an attractive delivery strategy for CRISPR-mediated genome editing due to their low immunogenicity and application safety. The biomimetic materials delivery is involved in the improvement of cellular uptake of nanoparticle vectors, and the gene editing efficiency. In this review, we summarize the current delivery strategies of CRISPR/Cas systems based on biogenic materials such as viruses, bacteria, cells, bioactive substances, etc., focusing on the potential applications in disease research and therapy. Finally, the prospects and limitations of CRISPR-based systems in therapeutics are discussed.
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Zona pellucida treatment before CRISPR/Cas9-mediated genome editing of porcine zygotes.
BACKGROUND: Increasing the permeability of the zona pellucida (ZP) of oocytes before CRISPR/Cas9 electroporation may improve the efficiency of gene editing; however, the effects of this approach on subsequent developmental processes are unclear. In this study, the effects of ZP treatment before electroporation on embryonic development and gene editing in porcine embryos were evaluated. METHODS: The ZP of zygotes was weakened or removed by exposure to 0.5% actinase E, followed by electroporation of the Cas9 protein with guide RNA targeting GGTA1. RESULTS: The blastocyst formation rate of ZP-free zygotes after electroporation was significantly lower (p < 0.05) than that of ZP-intact zygotes. The mutation rate in blastocysts from ZP-weakened zygotes was similar to that in ZP-intact zygotes, whereas ZP removal increased the mutation rate. The mutation efficiency in blastocysts from electroporated zygotes did not differ among ZP treatment groups. CONCLUSIONS: Our results indicate that weakening the ZP does not affect the developmental competence, mutation rate, or mutation efficiency of electroporated zygotes, whereas ZP removal has a detrimental effect on embryonic development but may increase the mutation rate.
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CRISPR/Cas: An intriguing genomic editing tool with prospects in treating neurodegenerative diseases.
The CRISPR/Cas genome editing tool has led to a revolution in biological research. Its ability to target multiple genomic loci simultaneously allows its application in gene function and genomic manipulation studies. Its involvement in the sequence specific gene editing in different backgrounds has changed the scenario of treating genetic diseases. By unravelling the mysteries behind complex neuronal circuits, it not only paved way in understanding the pathogenesis of the disease but helped in the development of large animal models of different neuronal diseases; thereby opened the gateways of successfully treating different neuronal diseases. This review explored the possibility of using of CRISPR/Cas in engineering DNA at the embryonic stage, as well as during the functioning of different cell types in the brain, to delineate implications related to the use of this super-specialized genome editing tool to overcome various neurodegenerative diseases that arise as a result of genetic mutations.
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Development of gene editing strategies for human β-globin (HBB) gene mutations.
Recent developments in gene editing technology have enabled scientists to modify DNA sequence by using engineered endonucleases. These gene editing tools are promising candidates for clinical applications, especially for treatment of inherited disorders like sickle cell disease (SCD). SCD is caused by a point mutation in human β-globin gene (HBB). Clinical strategies have demonstrated substantial success, however there is not any permanent cure for SCD available. CRISPR/Cas9 platform uses a single endonuclease and a single guide RNA (gRNA) to induce sequence-specific DNA double strand break (DSB). When this accompanies a repair template, it allows repairing the mutated gene. In this study, it was aimed to target HBB gene via CRISPR/Cas9 genome editing tool to introduce nucleotide alterations for efficient genome editing and correction of point mutations causing SCD in human cell line, by Homology Directed Repair (HDR). We have achieved to induce target specific nucleotide changes on HBB gene in the locus of mutation causing SCD. The effect of on-target activity of bone fide standard gRNA and newly developed longer gRNA were examined. It is observed that longer gRNA has higher affinity to target DNA while having the same performance for targeting and Cas9 induced DSBs. HDR mechanism was triggered by co-delivery of donor DNA repair templates in circular plasmid form. In conclusion, we have suggested methodological pipeline for efficient targeting with higher affinity to target DNA and generating desired modifications on HBB gene.
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Gene editing advance re-ignites debate on the merits and risks of animal to human transplantation.
In Australia, and internationally, the shortage of organ and tissue donors significantly limits the number of patients with critical organ or tissue failure who are able to receive a transplant each year. The rationale for xenotransplantation - the transplantation of living cells, tissues or organs from one species to another - is to meet this shortfall in human donor material. While early clinical trials showed promise, particularly in patients with type I diabetes whose insulin dependence could be temporarily reversed by the transplantation of porcine islet cells, these benefits have been balanced with scientific, clinical and ethical concerns revolving around the risks of immune rejection and the potential transmission of porcine endogenous retroviruses or other infectious agents from porcine grafts to human recipients. However, the advent of CRISPR/Cas9, a revolutionary gene editing technology, has reignited interest in the field with the possibility of genetically engineering porcine organs and tissues that are less immunogenic and have virtually no risk of transmission of porcine endogenous retroviruses. At the same time, CRISPR/Cas9 may also open up a myriad of possibilities for tissue engineering and stem cell research, which may complement xenotransplantation research by providing an additional source of donor cells, tissues and organs for transplantation into patients. The recent international symposium on gene editing, organised by the US National Academy of Sciences, highlights both the enormous therapeutic potential of CRISPR/Cas9 and the raft of ethical and regulatory challenges that may follow its utilisation in transplantation and in medicine more generally.
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Agrobacterium-Mediated Transformation for Gene Editing Tomato Elite Breeding Lines.
Genome editing success in crop species is largely dependent on the availability of highly efficient plant transformation protocols. Tomato (Solanum lycopersicum) was the first dicotyledonous crop to be successfully mutagenized using CRISPR-Cas9. Despite many efforts, no standardized, simple protocol is available for non-model tomato genotypes. With the increasing availability of gene editing tools, the transformation of elite tomato breeding lines has gained importance because mutant variants can be easily incorporated into breeding programs. This chapter describes a protocol for transforming and gene editing in elite tomato breeding lines, reaching 3.6% transformation efficiency.
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Strategies for Interdisciplinary Human Gene Editing Research: Insights from a Swiss Project.
CRISPR gene editing is a cutting-edge technology that has advanced tremendously in recent years. The first clinical CRISPR applications have been approved, and more gene editing therapies are to be expected in human medicine. Consequently, continuous basic research is needed to assess possibilities and prime future clinical applications. Because this technology not only offers new possibilities for treating diseases but also raises important ethical and societal questions, collaboration between human, life, biomedical, and medical sciences is needed. In this article, we discuss the practical challenges of such interdisciplinary projects and present strategies for addressing them based on our experience of conducting an interdisciplinary project on CRISPR. This work aims to help and encourage interdisciplinary collaborations and discussions on modern scientific endeavors that, such as gene editing, tend to blur the lines between traditional disciplines. The strategies suggested include realistic expectations, shared goals, space setting, and expert and lay dialogue.
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Discovery and engineering of AiEvo2, a novel Cas12a nuclease for human gene editing applications.
The precision of gene editing technology is critical to creating safe and effective therapies for treating human disease. While the programmability of CRISPR-Cas systems has allowed for rapid innovation of new gene editing techniques, the off-target activity of these enzymes has hampered clinical development for novel therapeutics. Here, we report the identification and characterization of a novel CRISPR-Cas12a enzyme from Acinetobacter indicus (AiCas12a). We engineer the nuclease (termed AiEvo2) for increased specificity, protospacer adjacent motif recognition, and efficacy on a variety of human clinical targets. AiEvo2 is highly precise and able to efficiently discriminate between normal and disease-causing alleles in Huntington's patient-derived cells by taking advantage of a single nucleotide polymorphism on the disease-associated allele. AiEvo2 efficiently edits several liver-associated target genes including PCSK9 and TTR when delivered to primary hepatocytes as mRNA encapsulated in a lipid nanoparticle. The enzyme also engineers an effective CD19 chimeric antigen receptor-T-cell therapy from primary human T cells using multiplexed simultaneous editing and chimeric antigen receptor insertion. To further ensure precise editing, we engineered an anti-CRISPR protein to selectively inhibit off-target gene editing while retaining therapeutic on-target editing. The engineered AiEvo2 nuclease coupled with a novel engineered anti-CRISPR protein represents a new way to control the fidelity of editing and improve the safety and efficacy of gene editing therapies.
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