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Molecular Biology and Gene Therapy
Published in R James A England, Eamon Shamil, Rajeev Mathew, Manohar Bance, Pavol Surda, Jemy Jose, Omar Hilmi, Adam J Donne, Scott-Brown's Essential Otorhinolaryngology, 2022
The future of restoring function via correction of genetic defects found in cancer may lie with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated nuclease 9 (Cas9) gene editing. CRISPR-Cas9 utilises the DNA cutting action of the Cas9 protein to create double-stranded DNA breaks, has relative high efficiency and accuracy for disruption gene transcription and can be adapted for editing gene transcription. Safety trials for the delivery of CRISPR-edited T cells into patients have started.
CRISPER Gene Therapy Recent Trends and Clinical Applications
Published in Yashwant Pathak, Gene Delivery, 2022
Prachi Pandey, Jayvadan Patel, Samarth Kumar
The knowledge of the biology of the CRISPR–Cas9 system is required for genome editing. The intensification in cleavage specificity of Cas9, and also the lessening of off-target activity of this enzyme, precisely enables to acknowledge particular target DNA sequences so as to edit or modify the genome accurately. CRISPR databases and tools provide detailed information and proper facility for altering, modifying, or visualizing genomes to conduct correct genome editing experiments. It is seen that CRISPR–Cas9 technology has been utilized in various fields, including disease treatment associated with genetic disorders or pathogens, recombinant DNA technology, agriculture, and clinical applications. However, many challenges have to be overcome.
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.
Shaping the future from the small scale: dry powder inhalation of CRISPR-Cas9 lipid nanoparticles for the treatment of lung diseases
Published in Expert Opinion on Drug Delivery, 2023
Simone P. Carneiro, Antonietta Greco, Enrica Chiesa, Ida Genta, Olivia M. Merkel
Lung diseases are some of the most lethal and disabling conditions occurring worldwide, resulting from genetic and environmental causes. CRISPR-Cas9 has been defined as one of the most revolutionary and innovative technologies that has opened a new therapeutic era for treating diseases cause by genetic mutations. CRISPR-Cas9 shows several strengths, one of which is its versatility in terms of application, therapeutic functions, and delivery forms and strategies broadly classified into physical, viral-vector, and non-viral vector delivery. In general, physical delivery approaches are difficult to be applied in vivo and viral vectors can potentially trigger pathological conditions. This leads to developing customizable non-viral DSs capable of addressing pharmacokinetic limitations based on the CRISPR-Cas9 form and administration route. In these regards, LNPs have attracted strong attention due to their ability to efficiently encapsulate and protect all three CRISPR-Cas9 forms enhancing and supporting genome editing.
Progress of delivery methods for CRISPR-Cas9
Published in Expert Opinion on Drug Delivery, 2022
Wu Yang, Jiaqi Yan, Pengzhen Zhuang, Tao Ding, Yu Chen, Yu Zhang, Hongbo Zhang, Wenguo Cui
The CRISPR-Cas9 system has also been used for gene-editing of other diseases, including sickle cell disease (SCD), transfusion-dependent β-thalassemia (TDT), and transthyretin amyloidosis (ATTR). A study by Frangoul et al. included a patient with SCD and a patient with TDT [130]. The CRISPR-Cas9 was used to target the enhancer of the BCL11A gene to induce the expression of γ-globin in hematopoietic stem and progenitor cells (HSPCs) from patients [130]. The results showed persistent implantation of HSPCs, a high level of fetal hemoglobin, and elimination of episodes of vascular obstruction or the need for blood transfusion [130]. Gillmore et al. conducted a clinical trial that included six patients with ATTR [131]. The LNPs-based CRISPR-Cas9 systems were injected into the patients with a single dose to knock out TTR [131]. The results showed that the serum concentration of TTR was reduced by more than 50% [131]. These preliminary explorations suggest that CRISPR-Cas9 has excellent potential for clinical application. However, more and more extended studies are still needed to evaluate the safety of CRISPR-Cas9 applications with humans. These clinical trials are shown in Table 4.
Emerging medicines to improve the basic defect in cystic fibrosis
Published in Expert Opinion on Emerging Drugs, 2022
Isabelle Fajac, Isabelle Sermet-Gaudelus
Gene editing repairs mutations in the CFTR gene and is mutation-specific. It is based on the delivery into target cells of both the correct version of the CFTR DNA sequence and a nuclease. The nuclease causes a break in the DNA near the mutation site and this break triggers recombination and DNA reparation. Nucleases used are Zinc Finger nucleases (ZFNs), Transcription activator-like effector nucleases (TALENs) and Clustered Regularly Interspersed Palindromic Repeats (CRISPR)/CRISPR-associated nuclease 9 (Cas9). CRISPR/Cas9 is targeted to a specific chromosomal site by guide RNAs. Its simple use, low cost, and anticipated low risk of off-target breaks has made CRISPR/Cas9 the main approach of gene editing studies in CF [33,42]. The first proof-of-concept study was published in 2013 and showed repair of the F508del mutation by gene editing in intestinal organoids [43]. Many other in vitro studies have followed [44]. No clinical study in CF has been undertaken yet with this approach which requires the use of effective delivery technology (Table 1). Outside the field of CF, clinical trials are underway to evaluate these therapeutic approaches for the treatment of cancer and sickle cell disease [45].