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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
However, for this approach to work, sequence selectivity is a crucial issue. It has been calculated that it may be necessary to actively recognize between 15 and 20 base pairs of DNA or RNA in order to selectively target one gene in the entire human genome (approximately 30,000 genes) (Figure 5.57). Many suitable gene targets have been identified during the past few decades and now await the development of effective gene-targeting technologies (Figure 5.59). Based on statistical calculations, a DNA-sequence-reading drug capable of recognizing approximately 15 DNA base pairs or more may be required in order to target a single gene in the entire human genome.
Transforming Growth Factor-β: A Cytokine Paradigm
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Michelle R. Frazier-Jessen, Nancy McCartney-Francis, Sharon M. Wahl
Transforming growth factor-β is a homodimeric protein of which there are Five known isoforms. Of these, only TGF-β1, -β2, and -β3 have been demonstrated in mammalian tissues. The TGF-βs belong to a superfamily of structurally related regulatory proteins that include activins, inhibins, Müllerian inhibiting substance, and the bone morphogenetic proteins [5]. TGF-β1, -β2, and -β3 are each encoded by unique genes on separate chromosomes, yet they share roughly 70%-80% amino acid sequence homology. Expression and activity of the TGF-β isoforms are regulated at transcriptional and translational levels, involving transcription factor-promoter interactions, message stability, processing, and secretion [5,6]. Although the biological activities of these isoforms are nearly indistinguishable in vitro, their sites and mechanisms of synthesis and in vivo localization are often distinct. In vitro, all three isoforms bind to the same receptors and induce similar responses, making them to some degree interchangeable. Yet the consequences of gene targeting suggest that the individual isoforms are dramatically different [7–11].
The Stress Response and Stress Proteins
Published in John J. Lemasters, Constance Oliver, Cell Biology of Trauma, 2020
Martin E. Feder, Dawn A. Parsell, Susan L. Lindquist
Can tolerance be engineered in multicellular animal models? Gene targeting is one technique that may soon provide answers to this question, but it is presently limited to a few model systems. Without targeting, however, insertion of transgenes in germ-line transformation experiments may inadvertently disrupt essential genes or alter their expression, which can obfuscate the phenotype of the transgene. Golic and Lindquist35 developed an approach that can alleviate this difficulty: The genome is transformed with a construct bearing a transgene of interest between two site-specific recombination targets from yeast. A separate transgene construct bears the region coding for the yeast FLP recombinase protein under control of an inducible promoter. When induced, FLP recombinase will catalyze recombination between sister chromatids bearing FLP recombination targets, producing a chromosome carrying multiple copies of the transgene or a chromosome lacking extra copies but interrupted at the exact same point as the extra copy chromosome. Multiple recombination events can be used to create an allelic series of chromosomes with a common point of transgene disruption but differing in transgene number. Subsequent genetic crosses can then isolate these chromosomes.
Effect of epithelial-specific MyD88 signaling pathway on airway inflammatory response to organic dust exposure
Published in Journal of Immunotoxicology, 2023
Amber N. Johnson, John Dickinson, Amy Nelson, Rohit Gaurav, Katrina Kudrna, Scott E. Evans, Katherine Janike, Todd A. Wyatt, Jill A. Poole
Targeted deletion of alleles can be achieved using Cre/Lox technology, wherein LoxP sites are inserted flanking an exon of interest and Cre recombinase is expressed under the control of cell-specific promoter (Wang 2009). This approach circumvents potential confounding issues of conventional gene-targeting approaches, including the unknown impact that global gene deletion may have on numerous cell and tissue types outside the area of study, and the possibility of overexpression in global transgenic approaches. The major lung epithelial cell types include ciliated cells, secretory cells, serous cells, and basal cells in the airways, and Type I and Type II pneumocytes in the alveoli (Singh and Katyal 2000). Although expression of surfactant protein C protein (SPC) is a marker Type II pneumocytes in postnatal mice, when under control of the Sftpc promoter, Cre recombinase is expressed in all these cell types during embryogenesis, allowing deletion of alleles (i.e. alleles that are floxed) throughout the lung epithelium. In comparison, the club cell-specific protein (CCSP) Cre mouse targets secretory epithelial cells diffusely expressed throughout the airways (Rawlins et al. 2009). Thus, using genetically engineered mouse lines, MyD88 deficiency can be localized to airway epithelial cells such that studies could then be undertaken to inform the specific roles of airway epithelial cells throughout the lung compartments.
Evolving treatments in high-risk neuroblastoma
Published in Expert Opinion on Orphan Drugs, 2020
Abhinav Kumar, John P J Rocke, B Nirmal Kumar
Immunotherapy is a growing field of cancer therapy; with interventions such as immune checkpoint blockades and cancer vaccines being developed. The incorporation of dinutuximab beta as a standard maintenance therapy highlights the importance of GD2 targeting for neuroblastomas. Further treatments exploiting the neuroblastoma cell expression of GD2 can be beneficial as immunotherapy seeks to improve treatment efficacy whilst reducing treatment-associated toxicities seen in conventional cytotoxic therapies. Personalized molecular therapies for neuroblastoma have been met by barriers such as resistance mechanisms and tumor heterogeneity that have reduced efficacy in pre-clinical trials. However, as our understanding of the genomic causes evolves, molecular therapies and newer generation drugs that target genetic abnormalities could play an important role in individualizing care for specific high-risk patients. This review highlights the important breakthroughs in both immunotherapy and gene targeting that could allow for a more effective maintenance therapy.
Combining cell and gene therapy to advance cardiac regeneration
Published in Expert Opinion on Biological Therapy, 2018
Pina Marotta, Eleonora Cianflone, Iolanda Aquila, Carla Vicinanza, Mariangela Scalise, Fabiola Marino, Teresa Mancuso, Michele Torella, Ciro Indolfi, Daniele Torella
One of the most advantageous property of genome editing tools is that they can be used to produce permanent changes within the genome. In principle, a single short-term application of an in vivo genome editing therapy could result in a lifelong therapeutic effect. There are three general therapeutic approaches for the gene targeting: first, the use the NHEJ to disrupt a gene that causes or contributes to a disease; second, the use of HDR to correct a gene mutation that causes a disease; and third, the use of HDR to insert a gene that will treat the disease (Figure 2). All these three approaches have potential to be implemented for cardiac regeneration. iPSCs from a patient with a known genetic disease could be generated editing them to correct the disease-generating mutation, differentiating the edited iPSC into the desired cell type (such as cardiomyocytes), and transplanting the differentiated cells back to the same patient. Moreover, as foreseen above, genetically engineered allogeneic CSCs could be an evaluable tool to boost the cardiac endogenous regeneration. In this regard, to avoid insertional mutagenesis and position effects, the safer method to insert a transgenic DNA in a cell is by site-directed insertion in a specific ‘safe-harbor’ locus, such as the AAVS1 locus, which has proven dispensable for human ES and somatic cells [125]. Genome editing would be an invaluable approach to insert the transgenic expression cassette for a regenerative factor in a targeted manner exploiting the HDR following an endonucleases-induced DSB using CRISPR/Cas9 system.