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Bioengineering and the Idea of Precision Medicine
Published in Emmanuel A. Kornyo, A Guide to Bioethics, 2017
Currently, there are four forms of gene editing biotechnologies or methods in use. They are Clustered regularly interspaced short palindromic repeats (CRISPR) Cas9Zinc finger nucleases (ZFN)9Transcription activator-like effector nucleases (TALENs)Meganuclease-reengineered homing endonucleases
Host Defense and Parasite Evasion
Published in Eric S. Loker, Bruce V. Hofkin, Parasitology, 2015
Eric S. Loker, Bruce V. Hofkin
Therefore, special mechanisms may need to be employed. For example, selfish genetic elements such as homing endonuclease genes could be used to drive the genes conferring resistance into natural populations. These selfish elements encode endonucleases that cleave a particular site in the genome and then effectively insert the genes encoding the endonuclease (and potentially engineered to contain anti -Plasmodium factors, too) into the cleaved site. In this way, they continually spread to other homologous sites that lack the endonuclease genes, inevitably becoming more common in the process. Some evidence suggests these drive mechanisms will work. If further work shows conclusively that we can successfully drive genetic elements conferring resistance into mosquito populations, then we also need to be sure that engineered Plasmodium-refractory mosquitoes are not also more refractory to all other mosquito pathogens as well; it would not be a good outcome to release super disease-resistant mosquitoes that then might become even more abundant than they already are. Also, this approach could quickly select for variants of Plasmodium that can overcome the engineered resistance genes. Although these may prove to be insurmountable problems, it can be argued we have nonetheless learned a great deal about mosquito biology, and this knowledge has paid off in other ways. For example, dengue virus vectors such as Aedes aegypti have been successfully infected with Wolbachia bacterial symbionts (see Chapters 2, 7, and 9 for more discussion of Wolbachia). These bacteria are close relatives of Wolbachia from Drosophila that are known to skew sex ratios, kill male flies, and favor fertilization only by males that are also infected. In the case of Wolbachia-bearingA. aegypti, they can spread upon release into natural populations and replace Wolbachia-freeA. aegypti. Furthermore, the bacterial infection is pathogenic enough to kill many dengue-infected mosquitoes before they can transmit the infection to another person. A similar goal—to reduce longevity of the infected vector below the developmental time required by the vectored parasite—could also be used to prevent Plasmodium infections from achieving sporozoite production (see Chapters 6 and 9). A similar approach could also be pursued for larval schis-tosomes developing in snails, which also take a long time to develop relative to the life spans of their snail hosts. That is, a way forward may be to exploit our knowledge of vector or intermediate host immunology just enough to prevent transmission from occurring.
Advances in Genome Editing
Published in Yashwant Pathak, Gene Delivery, 2022
Genetics is in a fantastic place right now, thanks to improvements in genetic analysis and manipulation. Gene therapy is the process of changing or introducing new genes to a person’s genome in order to treat or increase their ability to tackle disease. One facet of gene therapy is genome editing. Existing gene therapy procedures are founded on the findings of longer apparent laboratory investigations on individual cells and nonhuman species, demonstrating the ability to complement, eliminate, or alter genes in living beings. The advent of very adaptable genome-editing technology has given researchers the ability to rapidly and cost-effectively incorporate sequence-specific alterations into the genomes of a wide spectrum of cell types and organisms over the past few years (Metje-Sprink et al. 2019, Tsanova et al. 2021). The invention of genetic engineering in the late 20th century ushered in a new era in genome editing (Scherer and Davis, 1979; Rothstein, 1983; Smithies et al., 1985; Thomas et al., 1986). The true origins of this technique can be traced back to forerunners in genome engineering (Ishino et al., 1987; Nakata et al., 1989). Basically, genome editing refers to the employment of molecular tools, wherein genomic DNA is sliced in certain sites to facilitate tailored changes in the DNA pattern. These DNA splits then initiate cellular DNA repair processes, allowing site-specific epigenetic amendments to be introduced more easily (Bibikova et al., 2002; Urnov et al., 2005) (Figure 2.1). Initially, investigators found that when a length of DNA with similar arms on both ends is put into a cell, it may be assimilated into the host genome by homologous recombination and can control desired modifications in the cell (Capecchi 1989). However, the technique was limited to only dividing cells (Saleh-Gohari and Helleday, 2004). Later, more robust and effective gene targeting was achieved by the introduction of the double stranded break at a definite genomic target. The activation of cellular DNA repair mechanisms is then triggered, allowing for the insertion of site-specific genomic alterations. (Rouet et al., 1994). Several gene editing strategies have concentrated on the innovation and application of various endonuclease-based mechanisms to produce these breaks with high accuracy (Jacinto et al., 2020). Specifically, zinc finger nucleases (ZFNs), transcription activator-like effector nuclease (TALENs), meganucleases or homing endonucleases (MegNs), and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) are four key sites-specific genome editing strategies that have cleared the path for potential agricultural and medical advancements. In recent years, the genome editing technique is used fruitfully in varied clinical applications (Foss et al., 2019; Memi et al., 2018; Mahmoudian-sani et al., 2018). The chapter focuses on genome editing tools and its applications in treatment of various diseases employing nano delivery systems.
Advances in determining new treatments for hepatitis B infection by utilizing existing and novel biomarkers
Published in Expert Opinion on Drug Discovery, 2023
Lung-Yi Mak, Rex Wan-Hin Hui, Ka-Shing Cheung, James Fung, Wai-Kay Seto, Man-Fung Yuen
Some more classes of agents are currently being evaluated in the pre-clinical phase. Dihydroquinolizinone compounds (e.g. RG7834) are an orally available small molecule that binds to host proteins PAPD5/7 and destabilize HBV mRNA[96]. Drugs that target the cccDNA adopt either a gene editing or non-gene editing approach. For gene editing approach, nucleases can be designed to cleave a specific DNA sequence, e.g. in the S gene or episomal cccDNA, and lead to gene disruption and eventually inactivation of the gene. These include zinc finger proteins, transcription activator-like effector nucleases, clustered regularly interspaced short palindromic repeats (CRISPR) with CRISPR-associated 9 (Cas9), and homing endonucleases [97–103]. In the non-gene editing approach, the APOBEC3B pathway can be amplified and give rise to similar effects as PEG-IFNα [38]. The cccDNA destabilization can also be achieved via alternative pathways (e.g. ccc_R08). HBx is a potential target as it is heavily involved in regulating cccDNA transcription. HBx destroys a host of restrictive structural maintenance of chromosome (SMC) complex that is responsible for inhibition of viral transcription [104,105]. The NEDD8-activating enzyme (NAE) responsible for degrading SMC5/6 can be inhibited (e.g. Pevonedistat) and restore SMC5/6 function. [106] HBx can also be destabilized by NAPDH quinone oxidoreductase (NQO1) inhibitor (e.g. Dicoumarol). [107]
Gene therapy for primary immunodeficiencies: up-to-date
Published in Expert Opinion on Biological Therapy, 2021
Engineered nucleases create DSBs by recognizing target sites on genomic loci [86]. Four main nucleases have been developed over time: homing endonuclease (meganuclease), zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and the clustered regularly interspaced short palindromic repeat-associated protein 9 (CRISPR-Cas9). CRISPR-Cas9 is a monomer developed from the bacterial adaptive immune system, most commonly streptococcus pyogenes, and is popular due to its cost-effectiveness and ease of use. It uses a single chimeric guide RNA (gRNA) directing Cas9 to recognize a target site, and has the advantage of being programmable by altering gRNA’s, which can direct cleavage to the desired locus.