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Science Communication and Viruses
Published in Patricia G. Melloy, Viruses and Society, 2023
Some of the same organizers of the 1975 Asilomar meeting did participate in the 2015 Innovative Genomics Initiative Forum on Bioethics held in Napa, California. They met to discuss the germline modification of organisms, considering the new CRISPR gene-editing tool making such genomic modifications easier to execute. Germline modifications involve genetic changes that are passed onto the next generation, not just an altering of the adult or somatic cells of the body to correct a disease. This group of scientists made a statement discouraging germline modification of the human genome and called for the establishment of bioethical discussion including scientists and nonscientists. They also called for more research on the applications of CRISPR-Cas9 technology. Finally, they called for a meeting of international scientists, policy makers, and other leaders in the field to discuss this issue (Baltimore et al. 2015). The International Summit on Human Gene Editing was held the same year, and the group concluded that the needed safety precautions were not yet in place to do germline human gene editing safely. They recommended that a standing international group or committee be created to reexamine gene editing when more research data became available (National Academies of Sciences and Medicine 2015). In the future, can our national and international institutions build more of a framework to accommodate policy dialogue on rapidly emerging technologies? We need to consider as a society how to formalize public engagement with scientists.
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In the cancer area, most gene therapy approaches utilize adeno-associated viruses (AAVs) and lentiviruses to perform gene insertions both in vivo and ex vivo, respectively. The introduction of CRISPR gene editing (see Section 5.7.2.1.7) has provided new possibilities for gene therapy. The most common goal is to replace a mutated gene in a tumor cell with a working copy (e.g., a mutated tumor-suppressor p53 gene). This is usually attempted using an organ-specific viral vector such as a genetically engineered hepatovirus which can deliver a new gene to cells in the liver. Adenoviruses have also been extensively investigated for this purpose; however, there are two main problems. First, in terms of efficacy, experiments in both in vivo models and humans have shown that viral vectors rarely infect all cells in a tumor mass, and so the treatment is only partially effective with unaffected viable tumor cells maintaining tumor growth. Second, in terms of safety, organ-specific viral vectors are rarely completely specific for the target organ, and collateral infection of healthy cells can occur. This is regarded as a serious problem as previous clinical trials in children aimed at replacing a faulty metabolism-linked gene have shown that some individuals developed leukemia after the gene therapy, thought to be caused by collateral genomic damage of healthy cells.
Genetics
Published in Frank J. Dye, Human Life Before Birth, 2019
In research published during 2017, researchers claimed to have used CRISPR gene-editing technology to repair a genetic mutation causing heart disease in human embryos. This claim will have to be independently confirmed to dispel questions about whether what is claimed has actually been accomplished. And, of course, there are many ethical issues that need to be addressed regarding research carried out on human embryos.
Transcription activator-like effector nuclease (TALEN) as a promising diagnostic approach for COVID-19
Published in Expert Review of Molecular Diagnostics, 2022
Emad Behboudi, Parisa Zeynali, Vahideh Hamidi-Sofiani, Britt Nakstad, Alireza Tahamtan
Among different novel diagnostic methods, clustered regulatory, interspaced, short palindromic repeat (CRISPR), zinc-finger nucleases (ZFN), and transcription activator-like effector nuclease (TALEN) approaches are promising due to their programmability and ability to detect a specific location in the nucleic acid, i.e. site-specificity [4]. CRISPR is widely used in functional gene screening, cell-based human hereditary disease modeling, epigenetic studies, and visualization of cellular processes [5]. It is known as a rapid technology that quickly amplifies nucleic acid, with extremely high specificity and sensitivity. This assay is simple, efficient, and reliable and can distinguish differences in sequences of genomic targets. CRISPR gene editing is possible by ‘molecular scissors’ for cutting DNA threads that alter a piece of DNA. For example, new CRISPR-based technologies allow specific, multiplexed, portable, and ultrasensitive detection of RNA and DNA from clinically relevant samples [6]. An important approach toward developing CRISPR-based molecular diagnostics was discovering the collateral activity of Cas12 and Cas13 proteins [7]. A new version of CRISPR was introduced, called specific high-sensitivity enzymatic reporter unlocking (SHERLOCK), that incorporates genomic DNA strands with the CRISPR/Cas system to identify the targeted sequences [6]. Another CRISPR-based diagnostic tool is the DNA endonuclease-targeted CRISPR trans reporter (DETECTOR), a rapid (∼30 min), low-cost, and accurate CRISPR-Cas12-based lateral flow assay for diagnosis of viral infections [7].
Ophthalmic Implications of Chimeric Antigen Receptor T-Cell Therapy
Published in Seminars in Ophthalmology, 2021
Kevin D Chodnicki, Sashank Prasad
CAR T-cells can be produced from a patient’s own blood (autologous) or the blood of a donor (allogeneic). White blood cells are first harvested in a process called leukapheresis (figure 1). The harvested cells are then enriched in a process that removes inhibitory cell populations and stimulates the favored cells to proliferate. This population of T-cells is then infected with a retroviral vector (e.g., lentivirus), which integrates the necessary genetic information into the T-cells to allow expression of the desired receptor (e.g., CD19). Some techniques employ clustered regularly interspaced short palindromic repeats (CRISPR) gene editing techniques to insert the required gene modification instead of using viral vectors.9 This chimeric cell population is then expanded to the degree necessary for clinical use.10 In order to create space for the CAR T-cells to proliferate, patients often undergo lymphodepleting conditioning chemotherapy with medications including cyclophosphamide, fludarabine, or bendamustine. The process of obtaining, genetically engineering, and proliferating the T-cells can take several weeks. In most cases, the leukapheresis process is performed at the treating center with the cells then shipped to a commercial lab for preparation of the chimeric cells. The cells are cryopreserved in transit from the treating center and commercial lab. This commercial production process can cost over 350,000 USD per patient.10
Revising, Correcting, and Transferring Genes
Published in The American Journal of Bioethics, 2020
Most research to date on germline gene editing aims at what we can call correcting pathogenic mutations.7 The target is a disease-causing mutation. The goal of the editing is to remove the pathogenic mutation and alter the gene to match a nonpathogenic allele prevalent in the (healthy) population. These experiments have shown some success in achieving this goal, but outcomes also include a continued unacceptable rate of off-target effects. The mechanism used is usually the CRISPR gene editing platform, and the use of homology directed repair or non-homologous end joining at the cleaved site. The overall intention is, as in the title of one paper reporting an important example of this kind of editing (Ma et al. 2017), correction of pathogenic mutations for purposes of preventing the development of a monogenic disease in a prospective person.