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Genomic technologies
Published in Wendy A. Rogers, Jackie Leach Scully, Stacy M. Carter, Vikki A. Entwistle, Catherine Mills, The Routledge Handbook of Feminist Bioethics, 2022
In spite of the clinical promise of somatic genome editing, a variety of challenges are present, and more research is needed to try to address them (Stellos and Musunuru 2019; Hirakawa et al. 2020). For instance, some CRISPR-Cas9 components produce immunogenic reactions in certain individuals (Stellos and Musunuru 2019; Hirakawa et al. 2020). And in spite of its precision advantage, CRISPR-Cas9 gene-editing tools exhibit widespread off-target effects. Research groups worldwide are investigating these and other problems with genome editing technologies with the goal of making them sufficiently safe and effective as to become common therapy tools.
Current Application of CRISPR/Cas9 Gene-Editing Technique to Eradication of HIV/AIDS
Published in Yashwant Pathak, Gene Delivery, 2022
Prachi Pandey, Jayvadan Patel, Samarth Kumar
Recently, it had been demonstrated that Staphylococcus aureus Cas9 (SaCas9)/gRNAs in an all-in-one lentiviral vector could excise latent HIV-1 provirus and suppress provirus reactivation. Moreover, the combined SaCas9/gRNAs was observed to exhibit higher efficiency in disrupting the HIV-1 genome than single sgRNA mediated SaCas9 editing. Mutational inactivation of HIV-1 provirus by single sgRNA induced CRISPR/Cas9 editing has also been reported [39]. While targeting the LTR sequence and essential genes for viral replication by single sgRNA, the HIV-1 provirus was found to be inactivated by mutation of the target site. Thus, the virus can escape single gRNA mediated cleavage. This viral breakthrough may be alleviated by a combinatorial CRISPR/Cas9 gene-editing approach [40].
AI and Immunology Considerations in Pandemics and SARS-CoV-2 COVID-19
Published in Louis J. Catania, AI for Immunology, 2021
A new Cas13 RNA screen has been developed to establish guide RNAs for the COVID-19 coronavirus and human RNA segments which could be used in vaccines, therapeutics, and diagnostics. A novel CRISPR-based (see Section “CRISPR-Cas9 (Gene Editing)”, Chapter 4, page 77) editing tool enables researchers to target mRNA and knockout genes without altering the genome has been developed. Using the CRISPR-Cas13 enzyme, researchers have created a genetic screen for RNA, currently designed for use on humans, which they say could also be used on RNA containing viruses and bacteria.
Stereotaxic-assisted gene therapy in Alzheimer’s and Parkinson’s diseases: therapeutic potentials and clinical frontiers
Published in Expert Review of Neurotherapeutics, 2022
Samar O. El Ganainy, Tony Cijsouw, Mennatallah A. Ali, Susanne Schoch, Amira Sayed Hanafy
CRISPR/Cas9 gene editing strategies include delivering plasmid-borne CRISPR/Cas9 systems, Cas9/sgRNA complexes and Cas9-mRNA/sgRNA mixtures. In the last few years, an increasing number of studies implemented CRISPR/Cas9 strategies to silence or correct faulty genes encountered in sporadic as well as familial AD [97]. To our knowledge, most of these studies opted for directly injecting the therapeutic system into the brain, packaged as nanocomplexes with R7L10 peptides, recombinant adeno-associated viruses (AAVs) or lentivirus [122–124]. The targeted genes included BACE1 [122], KM670/671NL APP (APPswe) mutation [123] and APP at the extreme C-terminus [124]. These approaches successfully suppressed pathogenic Aβ and its associated cognitive deficits, reflecting its promising therapeutic impact in AD. However, some challenges can hinder its clinical application such as the difficulty to target widespread dysfunction in neural circuits and the risk for irreversible genomic alterations [122]. Multiple mismatches impose the risk of inducing genomic toxicity, carcinogenesis, or epigenetic alterations. Moreover, the relatively large size of Cas9 may render the loading of viral vectors challenging. However, adjusting the dosage and the use of double viral vectors could offer hope for a clinically successful application of CRISPR/Cas9 [125,126].
CRISPR/Cas9 gene editing therapies for cystic fibrosis
Published in Expert Opinion on Biological Therapy, 2021
Additionally, non-CRISPR-Cas9 gene editing therapies have recently been explored. TALEN-mediated homologous recombination was recently used to correct the F508del mutation in iPSCs, which were then expanded into intestinal organoids [101]. A TALEN plasmid was nucleofected alongside a donor vector carrying the desired mutation correction as well as a puromycin-resistance selection cassette flanked by PiggyBac transposon sites; after correction and selection, the selection cassette was removed via the PiggyBac system [101]. Corrected iPSCs showed CFTR protein abundance and localization comparable to non-CF cells; corrected and uncorrected iPSCs were then expanded into intestinal organoids [101]. CFTR function was assayed using FIS assay; upon exposure to forskolin, corrected organoids increased their surface area to 177%, while uncorrected organoids increased to 103%, with 100% representing the pretreatment surface area [101]. Additionally, corrected organoids were found to be responsive to the clinically approved double-combination drug VX-770/VX-809 (marketed as Orkambi), suggesting that DNA editing-based therapies can be combined with pharmaceutical intervention to enhance clinical outcome [101].
Delivering CRISPR: a review of the challenges and approaches
Published in Drug Delivery, 2018
Christopher A. Lino, Jason C. Harper, James P. Carney, Jerilyn A. Timlin
The most recently developed site-specific gene editing tool, CRISPR/Cas9, is a naturally occurring RNA-guided endonuclease. A methodical investigation by the scientific community has deciphered the natural function of the CRISPR/Cas9 gene editing system. Based on this work, several laboratories developed CRISPR/Cas9 as a tool that has now been applied in much of modern molecular biology. A key difference of this system from the protein-based binding to DNA of ZFNs and TALENs is the use of a short RNA sequence as the specificity-determining element to drive the formation of a DSB at the targeted site. The use of CRISPR/Cas9 avoids the need for protein engineering to develop a site-specific nuclease against a specific DNA target sequence, requiring only the synthesis of a new piece of RNA. This dramatically simplifies and greatly reduces the time needed for gene editing design and implementation.