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A Field Day for Gene-Edited Brassicas and Crop Improvement.
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Current Techniques of Gene Editing in Pigs for Xenotransplantation.
Shortage of human organs for transplantation has created a demand for alternative solutions of which xenotransplantation is amongst the most promising one in the short term. However, the immune reaction following transplantation of a pig organ is greater than the one elicited during allotransplantation. Genetic engineering of the pig is required so that pig organs or tissues are made less immunogenic to humans by eliminating some antigens and by expressing human proteins that can reduce the damage by the host immune system. To generate founder animals with the desired mutations genetic engineering of somatic cells with multiplexed mutations combined with somatic cell nuclear transfer (SCNT) is the best solution with the technology available today. Safety concerns include potential zoonosis, primarily porcine endogenous retroviruses (PERVs). Ethical considerations might arise from the use animals involved in research. Genome editing techniques based CRISPR-Cas9, have greatly facilitated the modification of pig's genome to address coagulation and inflammation issues, to mention just a few, arising after the pig organ is transplanted into a human. However, further research is needed to ensure safety and efficacy of the genome edits introduced in the pig genome are compatible with the health and welfare of the pigs.
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Models of Technology Transfer for Genome-Editing Technologies.
Many of the fundamental inventions of genome editing, including meganucleases, zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and CRISPR, were first made at universities and patented to encourage commercial development. This gave rise to a diversity of technology transfer models but also conflicts among them. Against a broader historical and policy backdrop of university patenting and special challenges concerning research tools, we review the patent estates of genome editing and the diversity of technology transfer models employed to commercialize them, including deposit in the public domain, open access contracts, material transfer agreements, nonexclusive and exclusive licenses, surrogate licenses, and aggregated licenses. Advantages are found in this diversity, allowing experimentation and competition that we characterize as a federalism model of technology transfer. A notable feature of genome editing has been the rise and success of third-party licensing intermediaries. At the same time, the rapid pace of development of genome-editing technology is likely to erode the importance of patent estates and licensing regimes and may mitigate the effect of overly broad patents, giving rise to new substitutes to effectuate commercialization.
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Correcting inborn errors of immunity: From viral mediated gene addition to gene editing.
Allogeneic hematopoietic stem cell transplantation is an effective treatment to cure inborn errors of immunity. Remarkable progress has been achieved thanks to the development and optimization of effective combination of advanced conditioning regimens and use of immunoablative/suppressive agents preventing rejection as well as graft versus host disease. Despite these tremendous advances, autologous hematopoietic stem/progenitor cell therapy based on ex vivo gene addition exploiting integrating γ-retro- or lenti-viral vectors, has demonstrated to be an innovative and safe therapeutic strategy providing proof of correction without the complications of the allogeneic approach. The recent advent of targeted gene editing able to precisely correct genomic variants in an intended locus of the genome, by introducing deletions, insertions, nucleotide substitutions or introducing a corrective cassette, is emerging in the clinical setting, further extending the therapeutic armamentarium and offering a cure to inherited immune defects not approachable by conventional gene addition. In this review, we will analyze the current state-of-the art of conventional gene therapy and innovative protocols of genome editing in various primary immunodeficiencies, describing preclinical models and clinical data obtained from different trials, highlighting potential advantages and limits of gene correction.
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Protocol for streamlining genotyping of germline-transmissible mutants from genome editing by using a parallel qPCR-based index and R analysis.
Targeted genome editing using CRISPR-Cas, ZFNs, or TALENs enables precise gene function studies but often produces point mutations or insertions or deletions (indels) that are difficult to detect by conventional PCR. We developed a parallel qPCR assay with an iGenotype index for simple, reliable genotyping. iGenotype values (1, 0, -1) remained constant across allele-specific primers. qPCR data can be analyzed via an R program, enabling large-scale or automated genotyping. For complete details on the use and execution of this protocol, please refer to Fu et al.1.
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A decade of public engagement regarding human germline gene editing: a systematic scoping review.
Following the discovery of the CRISPR-Cas technology in 2012, there has been a growing global call for public engagement regarding the potential use of human germline gene editing (HGGE). In this systematic scoping review, we aim to evaluate public engagement studies considering the following questions based on three points of attention: 1) Inclusion of underrepresented groups: who have been engaged? 2) Gathering values: what output has been reported? 3) Reaching societal impact: what objectives of public engagement have been reported? A systematic literature search from 2012 to 2023 identified 3464 articles reporting on public engagement studies regarding HGGE retrieved from 12 databases. After screening, 52 full-text articles were assessed for eligibility, resulting in 36 articles that cover 31 public engagement studies. We conclude that co-created efforts are needed to engage underrepresented groups as well as to yield values rather than acceptance levels, and to concretise how engagement might result in societal impact.
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Recent advances in genome editing of stem cells for drug discovery and therapeutic application.
Genome engineering technologies right from viral vector-mediated to protein-based editing- which include zinc finger nucleases, TALENs, and CRISPR/Cas systems-have been improved significantly. These technologies have facilitated drug discovery and have resulted in the development of potential curative therapies for many intractable diseases. They can efficiently correct genetic errors; however, these technologies have limitations, such as off-target effects and possible safety issues, which need to be considered when employing these techniques in humans. Significant efforts have been made to overcome these limitations and to accelerate the clinical implementation of these technologies. In this review, we focus on the recent technological advancements in genome engineering and their applications in stem cells to enable efficient discovery of drugs and treatment of intractable diseases.
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Lipid nanoparticle-mediated intracameral mRNA delivery facilitates gene expression and editing in the anterior chamber of the eye.
Lipid nanoparticles (LNPs) have shown great potential in the field of gene therapy for retinal diseases. To expand on this application, we investigated LNP-mediated mRNA delivery to the anterior chamber of the eye via the intracameral (IC) route of administration. Here, we show that IC injections of LNPs facilitated protein expression and gene editing in the trabecular meshwork (TM). Administration of Cre-mRNA LNPs to Ai9 mice resulted in robust tdTomato expression in the angle and corneal endothelium. In C57BL/6 mice, mCherry-mRNA LNPs demonstrated localized protein expression in the TM, which peaked at 72 h and subsequently declined over 120 h. Additionally, LNPs encapsulating Cas9 mRNA with sgAi9 enabled in vivo gene editing in Ai9 mice, with up to 14.3 % editing efficiency. This induced tdTomato expression in the iridocorneal angle, validating the potential of LNPs for gene editing applications. Importantly, no ocular toxicity was observed, indicating the safety of the IC LNP administration. Our findings highlight the use of LNPs for targeted gene therapy and editing, paving the path for the treatment of diseases such as glaucoma in the anterior eye.
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Genome editing in Streptococcus mutans through self-targeting CRISPR arrays.
Streptococcus mutans is the primary etiological agent of human dental caries. Its major virulence factors, glucosyltransferases (Gtfs), utilize sucrose to synthesize extracellular polysaccharides (EPS), leading to the formation of dental plaque biofilm. The current study was designed to develop a novel self-targeting gene editing technology that targeted gtfs to inhibit biofilms formation. The CRISPR-Cas system (ie, clustered regularly interspaced short palindromic repeat, with CRISPR-associated proteins) provides sequence-specific protection against foreign genetic materials in archaea and bacteria, and has been widely developed for genomic engineering. The first aim of this study was to test whether components of the CRISPR-Cas9 system from S mutans UA159 is necessary to defend against foreign DNA. The data showed that a suitable PAM site, tracrRNA, Cas9, and RNase III are indispensable elements to perform normal function of S mutans CRISPR-Cas9 system. Based on these results, we designed self-targeting CRISPR arrays (containing spacer sequences identifying with gtfB) and cloned them onto plasmids. Afterward, we transformed the plasmids and editing templates into UA159 (self-targeting) to acquire desired mutants. Our data showed that this technology performed well and was able to successfully edit gtfB or gtfBgtfC genes. This resulted in high reduction in EPS synthesis and was able to breakdown biofilm formation, which is also a promising tool for dental clinics in order to prevent the formation of S mutans biofilms in the future.
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CCR5 gene editing - Revisiting pros and cons of CCR5 absence.
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