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The kill-switch for CRISPR that could make gene-editing safer.
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The evolution and history of gene editing technologies.
Scientific enquiry must be the driving force of research. This sentiment is manifested as the profound impact gene editing technologies are having in our current world. There exist three main gene editing technologies today: Zinc Finger Nucleases, TALENs and the CRISPR-Cas system. When these systems were being uncovered, none of the scientists set out to design tools to engineer genomes. They were simply trying to understand the mechanisms existing in nature. If it was not for this simple sense of wonder, we probably would not have these breakthrough technologies. In this chapter, we will discuss the history, applications and ethical issues surrounding these technologies, focusing on the now predominant CRISPR-Cas technology. Gene editing technologies, as we know them now, are poised to have an overwhelming impact on our world. However, it is impossible to predict the route they will take in the future or to comprehend the full impact of its repercussions.
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Gene Editing Clinical Trials Could Slip through Australian Regulatory Cracks.
In this column we explore the regulatory environment within which clinical trials involving new genome editing techniques are undertaken. Ostensibly, there is regulatory congestion in this area, with overlapping obligations through the national scheme for regulating gene technology, the national scheme for regulating the supply of therapeutic goods, and the human research ethics system, predominantly administered at the institutional level. In practice, however, the oversight of gene editing clinical trials is left almost entirely to human research ethics committees. Given the uncertain risks associated with such novel technologies, we conclude that it is opportune to reconsider the rigour of current Australian processes for assessing clinical trials involving gene-editing technology.
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Optimization of Cas9 RNA sequence to reduce its unexpected effects as a microRNA sponge.
UNLABELLED: Cas9 RNA functions as a miRNA sponge. Let-7 is the dominant regulated miRNA by Cas9 RNA. RNA sequence optimization of Cas9 by synonymous mutation improves its safety. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-022-01604-x.
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A gene-edited mouse model of limb-girdle muscular dystrophy 2C for testing exon skipping.
Limb-girdle muscular dystrophy type 2C is caused by autosomal recessive mutations in the γ-sarcoglycan (SGCG) gene. The most common SGCG mutation is a single nucleotide deletion from a stretch of five thymine residues in SGCG exon 6 (521ΔT). This founder mutation disrupts the transcript reading frame, abolishing protein expression. An antisense oligonucleotide exon-skipping method to reframe the human 521ΔT transcript requires skipping four exons to generate a functional, internally truncated protein. In vivo evaluation of this multi-exon skipping, antisense-mediated therapy requires a genetically appropriate mouse model. The human and mouse γ-sarcoglycan genes are highly homologous in sequence and gene structure, including the exon 6 region harboring the founder mutation. Herein, we describe a new mouse model of this form of limb-girdle muscular dystrophy generated using CRISPR/Cas9-mediated gene editing to introduce a single thymine deletion in murine exon 6, recreating the 521ΔT point mutation in Sgcg These mice express the 521ΔT transcript, lack γ-sarcoglycan protein and exhibit a severe dystrophic phenotype. Phenotypic characterization demonstrated reduced muscle mass, increased sarcolemmal leak and fragility, and decreased muscle function, consistent with the human pathological findings. Furthermore, we showed that intramuscular administration of a murine-specific multiple exon-directed antisense oligonucleotide cocktail effectively corrected the 521ΔT reading frame. These data demonstrate a molecularly and pathologically suitable model for in vivo testing of a multi-exon skipping strategy to advance preclinical development of this genetic correction approach.
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CRISPR-Cas9 and the Promise of a Better Future.
Due to its simplicity, low cost and accuracy, CRISPR-Cas9 has become a promising new technique in the field of gene editing. However, despite its virtues, it is not yet immune to scientific hazards and ethical legal concerns. These concerns have been used to justify opposition to genetic manipulation, and have led to some regulations to ban or impose a moratorium based on the precautionary principle. In Europe, regulation mostly comes from the European Union and the Council of Europe, both very cautious towards gene editing. In this article, two arguments on the future legal framework of CRISPR-Cas9 are made. The first is that continued research will contribute to more scientific accuracy; thus, the precautionary principle should promote regulated research to achieve this aim. The second is that most of the legal and ethical concerns surrounding CRISPR-Cas9 are based on unfounded prejudice emanating from a mystical understanding of the human genome.
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Targeted DNA methylation in human cells using engineered dCas9-methyltransferases.
Mammalian genomes exhibit complex patterns of gene expression regulated, in part, by DNA methylation. The advent of engineered DNA methyltransferases (MTases) to target DNA methylation to specific sites in the genome will accelerate many areas of biological research. However, targeted MTases require clear design rules to direct site-specific DNA methylation and minimize the unintended effects of off-target DNA methylation. Here we report a targeted MTase composed of an artificially split CpG MTase (sMTase) with one fragment fused to a catalytically-inactive Cas9 (dCas9) that directs the functional assembly of sMTase fragments at the targeted CpG site. We precisely map RNA-programmed DNA methylation to targeted CpG sites as a function of distance and orientation from the protospacer adjacent motif (PAM). Expression of the dCas9-sMTase in mammalian cells led to predictable and efficient (up to ~70%) DNA methylation at targeted sites. Multiplexing sgRNAs enabled targeting methylation to multiple sites in a single promoter and to multiple sites in multiple promoters. This programmable de novo MTase tool might be used for studying mechanisms of initiation, spreading and inheritance of DNA methylation, and for therapeutic gene silencing.
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Move over, CRISPR: RNA-editing therapies pick up steam.
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Establishment of a CRISPR/Cas9 gene editing system based on growth points transformation method in Fraxinus mandshurica.
The lack of an effective gene editing technology system for Fraxinus mandshurica makes it challenging to improve its traits through genetic engineering methods. In this study, an effective CRISPR/Cas9 gene editing system targeting plant growth points was established through the optimization of Agrobacterium tumefaciens concentration and infection duration. Furthermore, a tissue culture system for clustered buds was developed by supplementing the media with hormones at different concentrations. FmbHLH1-edited chimeric plants were successfully generated using the developed CRISPR/Cas9 gene editing system. Homozygous plants were induced and screened using the developed clustered bud system. Among 100 randomly transformed growing points, 18% of the induced clustered buds were gene-edited, which confirmed that the established CRISPR/Cas9 gene editing system was effective. Phenotypic analysis and evaluation of drought tolerance-related physiological indicators in FmbHLH1 knockout and wild-type lines revealed that FmbHLH1 positively regulated the drought tolerance of F. mandshurica by adjusting its ability to scavenge reactive oxygen species and to regulate osmotic potential. In summary, we developed an effective CRISPR/Cas9 gene editing system for F. mandshurica, providing an effective method for the molecular breeding of F. mandshurica.
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Exploring the potential of genome editing CRISPR-Cas9 technology.
CRISPR-Cas9 is an RNA-mediated adaptive immune system that protects bacteria and archaea from viruses or plasmids. Herein we discuss the recent development of CRISPR-Cas9 into a key technology for genome editing, targeting, and regulation in a wide range of organisms and cell types. It requires a custom designed single guide-RNA (sgRNA), a Cas9 endonuclease, and PAM sequences in the target region. The sgRNA-Cas9 complex binds to its target and creates a double-strand break (DSB) that can be repaired by non-homologous end joining (NHEJ) or by the homology-directed repair (HDR) pathway, modifying or permanently replacing the genomic target sequence. Additionally, we highlight recent advances in the repurposing of CRISPR-Cas9 for repression, activation, and loci imaging. In this review, we underline the current progress and the future potential of the CRISPR-Cas9 system towards biomedical, therapeutic, industrial, and biotechnological applications.
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