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Should Genome Editing Replace Embryo Selection Following PGT?
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
In 2019, only seven years after CRISPR-Cas9-based genome editing was first described as a molecular biology tool (27,28), the birth of the first “CRISPR babies” Lulu and Nana was announced at a summit in Hong Kong. Gene editing had been applied at an embryonic stage in order to disrupt normal copies of the CCR5 gene, with the intention of conferring resistance to the HIV virus (the father of the children was HIV-positive). The announcement was met with condemnation from many quarters, not least from the scientific community. It was considered that the safety of the method had not been adequately demonstrated. In particular, there were concerns over the potential for inadvertent editing of unintended areas of the genome (i.e., off-target effects) and that there could be other unforeseen consequences of using CRISPR-Cas9 during early embryonic development. Additionally, many considered GE unnecessary, since there are well-validated “sperm washing” procedures, which avoid HIV transmission when using IVF. The two girls born as a result of the procedure are understood to have non-functional copies of CCR5. While this may provide the intended resistance to HIV infection, some evidence suggests there may also be negative health consequences of loss of CCR5 function, a problem that will be passed on to subsequent generations.
Health Professionals and Modern Human Research Ethics
Published in Howard Winet, Ethics for Bioengineering Scientists, 2021
The targeting ability of one of the Cas nucleases, Cas9 (from Streptococcus pyogenes) attached to a synthetic RNA complex (crRNA+tracrRNA), often referred to as a “guide RNA”, is crucial to the editing process. The ability of Cas9 to cleave almost any DNA site preceding a chemical signature called a PAM (Protospacer-Adjacent Motif), has made this nuclease a prime tool for the first step in genome editing (Salsman and Dellaire 2016). The CRISPR-Cas9 system has been used by a number of laboratories for mammalian cell genome editing since appearance of the “seminal” (Salsman and Dellaire 2016) publication of its success with DNA in 2012 (Jinek et al. 2012).
AI and Autoimmunity
Published in Louis J. Catania, AI for Immunology, 2021
The CRISPR-Cas9 system (Figure 4.3)63 creates a small piece of RNA with a short “guide” sequence that attaches (binds) to a specific target sequence of DNA identified by AI in a genome. The RNA also binds to the Cas9 enzyme and is used to recognize the DNA sequence. The Cas9 enzyme acting as a “scissor” cuts the DNA at the targeted location. Once the DNA is cut, the cell’s DNA uses its repair machinery to add or delete pieces of genetic material, or to make changes to the DNA by replacing an existing segment with a customized DNA sequence.64
Nanotechnology-enabled gene delivery for cancer and other genetic diseases
Published in Expert Opinion on Drug Delivery, 2023
Tong Jiang, Karina Marie Gonzalez, Leyla Estrella Cordova, Jianqin Lu
The delivery of gene therapeutics also encounters complex microenvironment in vivo at the same time, in which the nonspecific immunogenicity of nanomaterials and immunology-related molecular mechanisms involved. It is necessary to consider off-target effects and potential mutations in various carriers. For example, the Cas9 protein itself has been proved to trigger a humoral immune response, which can result in cytotoxicity in host cells. Besides, CRISPR/Cas9 delivery system has the continuous expression. Although the high expression level of Cas9 in cells will bring higher editing potential, once it was integrated into the genome, the expression of Cas9 is persistent and irreversible. The continuous expression in the host can lead to the unintentional ‘off-target’ editing in genome. The use of gene vectors can avoid the potential risks of off-target mutation and other genome integration to some extent.
Genetic and epigenetic mechanisms influencing acute to chronic postsurgical pain transitions in pediatrics: Preclinical to clinical evidence
Published in Canadian Journal of Pain, 2022
Adam J. Dourson, Adam Willits, Namrata G.R. Raut, Leena Kader, Erin Young, Michael P. Jankowski, Vidya Chidambaran
Epigenetic biomarkers are being developed for screening in some areas like cancer. They are also being used to develop therapeutic targets. Sun et al. found that DNA methyltranferase (DNMT) inhibitor 5-Aza-2ʹ-deoxycytidine significantly reduced incision-induced mechanical allodynia and thermal sensitivity.240 Although six epigenetic drugs are approved for use in the United States (many more under development), their nonspecific effects are a significant drawback (see reviews241,242). In addition to generalized epigenetic targeting approaches, gene-specific epigenetic targeting is becoming a possibility through recently developed genome editing technology (e.g., demethylation of specific CpGs in human cells using fusions of engineered transcription activator–like effector repeat arrays, TET1 hydroxylase catalytic domain) that can effectively target and demethylate individual genes in vitro.243 In addition, Cas9 systems offer novel individual gene targeted approaches.244 Interestingly, the beneficial effects of lifestyle modifications (e.g., exercise) on mechanical and thermal hypersensitivity after sciatic nerve injury245 are partially mediated by decreased HDAC activity and increased acetylation of histones in the spinal cord,246 pointing to the potential use of nonpharmacologic strategies targeting the epigenome in the management of CPSP.
Layer-by-Layer technique as a versatile tool for gene delivery applications
Published in Expert Opinion on Drug Delivery, 2021
Dmitrii S. Linnik, Yana V. Tarakanchikova, Mikhail V. Zyuzin, Kirill V. Lepik, Joeri L. Aerts, Gleb Sukhorukov, Alexander S. Timin
Delivery of genome-editing (GE) tools via non-viral carriers has become a widely studied research topic. LbL technology can promote nucleic acid delivery methods that can be used for non-viral delivery of genome-editing tools. One of the most promising GE methods is CRISPR/Cas9, for which Jennifer Doudna and Emmanuelle Charpentier recently received the Nobel prize. The Cas9 nuclease is targeted to a specific site in DNA with the help of a guide RNA (gRNA) sequence. Cas9 then makes a double-strand break (DSB) at the intended site, which is followed by the activation of DSB repair systems. The induced break can be repaired by non-homologous end joining (NHEJ), microhomology-mediated end joining (MMEJ), homology-mediated end joining (HMEJ), or homologous recombination (HR). Reparation of a double-strand break in targeted genes can result in deletions, insertions, or point mutations.