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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
When expression of a particular gene is the cause of a disease such as cancer, and the sequence of the gene is known, the antisense therapy approach involves the use of a strand of nucleic acid (DNA, RNA, or a chemical analog of either) to target the messenger RNA (mRNA) produced by that gene to inactivate it and turn the gene “off”. Various strategies include targeting the promoter or coding regions of genes, the splicing sites on pre-RNA, or modifications of the exons of mRNA segments.
Human Bcl-2 Antisense Therapy for Lymphomas
Published in Eric Wickstrom, Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, 2020
Finbarr E. Cotter, Andrew Webb, Paul Clarke, David Cunningham
Similar findings have been documented in a phosphorothioate human trial targeting p53 (Bishop et al., 1996). Four of the 9 patients developed an infection, none of which could be directly attributed to the antisense therapy. The only significant toxicity directly related to antisense therapy was a local skin reaction surrounding the infusion site. In 8 patients this simply required re-siting the line site every 3-4 days. However, one patient (patient 4) suffered a local inflammatory reaction that became unacceptablv painful about 12 hours after starting treatment. A skin biopsy from the inflamed area demonstrated increased infiltration of Τ lymphocytes. Despite several site changes and dilution of drug concentration by 50%, the inflammation persisted and treatment could not to be continued. Two patients treated subsequently at this dose level and 3 with a 100% dose increment did not experience the same degree of reaction.
Liposomes in the Delivery Of Antisense Oligonucleotides
Published in Danilo D. Lasic, LIPOSOMES in GENE DELIVERY, 2019
In antisense therapy there are predominantly two major problems: quick chemical degradation due to backbone instability and efficient delivery of these molecules into the cells. To reduce the degradation by nucleases inside and outside of the cells the biodegradable phosphodiester linkage is modified. As shown in Figure 12-2 the phosphodiester group (–O3PO–), which spans C3 and C5 carbon atoms on ribose molecules, can be changed into phosphorothioate (–O3PS–), methylphosphonate (–O3PCH3–), phosphoroamidate (–O3PN–alkyl), and some others. This substitution enhances the resistance of the oligomers to nucleases from minutes to hours and days with tolerable affinity. In fact, affinity of phosphorothioates to RNA and the ability to block the expression of SV40 lathe T antigene increased significantly when the propynepyrimidine group was linked to the C5 position on the base. Similarly, the c-ras protein expression was blocked more efficiently if sugars were modified by 2′-O-methyl or 2′-O-fluoro groups.
Current progress of miRNA-derivative nucleotide drugs: modifications, delivery systems, applications
Published in Expert Opinion on Drug Delivery, 2022
Charles Asakiya, Liye Zhu, Jieyu Yuhan, Longjiao Zhu, Kunlun Huang, Wentao Xu
MicroRNAs (miRNAs) are a category of relatively small single-stranded non-coding RNA molecules with the potential to treat a myriad of genetic diseases[1]. They inhibit protein synthesis at the post-transcriptional level and induce translational repression[2]. Since 1993, over 2000 miRNAs have been experimentally authenticated in humans and mammals [3,4]. miRNAs regulate over 60% of the protein-coding genes in the human genome [5,6]. Unlike siRNAs, miRNAs regulate multiple genes. While the former functions as antisense therapy (synthetic ssDNA are used to inhibit RNAs), the latter functions in two ways; antisense (use of antagonists/antimiRs to inhibit miRNAs) and replacement (use of miRNA mimics) therapies. This dysregulation feature of miRNAs in diseases led to miRNA-derivative clinical nucleotide drugs (mdCNDs).
Restoration of dystrophin expression and correction of Duchenne muscular dystrophy by genome editing
Published in Expert Opinion on Biological Therapy, 2021
Tejal Aslesh, Esra Erkut, Toshifumi Yokota
Most patients carrying in-frame deletion mutations present a milder condition known as Becker muscular dystrophy (BMD) than those with out-of-frame mutations [4]. Such in-frame mutations allow for the production of a truncated yet partially functional form of dystrophin protein, giving rise to the mild BMD phenotype. This laid the foundation for an exon-skipping approach to facilitate the conversion of out-of-frame mutations to in-frame ones and thereby lead to a milder phenotype. This is most commonly mediated by an approach known as antisense oligonucleotide-mediated exon skipping therapy wherein synthetically modified DNA/RNA nucleotides (antisense oligonucleotides, AONs) bind to the splicing enhancer sites (including cryptic splice sites) and exclude an exon from the final mRNA transcript [5]. Eteplirsen was the first AON targeting the skipping of exon 51 that was approved by the Food and Drug Administration (FDA), applicable to 13% of patients [6]. Additionally, golodirsen and viltolarsen have been recently approved to induce skipping of exon 53, applicable to approximately 8–10% of DMD patients [7]. Despite developments in the field of antisense therapy, there are prevalent issues including the necessity of repeated administrations, high treatment costs, and poor delivery of AONs to the heart due to limited uptake [8].
Emerging drugs for the treatment of acromegaly
Published in Expert Opinion on Emerging Drugs, 2020
Claudia Campana, Giuliana Corica, Federica Nista, Francesco Cocchiara, Giulia Graziani, Keyvan Khorrami, Marta Franco, Mara Boschetti, Diego Ferone, Federico Gatto
ATL-1103 is a second generation 2ʹ-O-(2-methoxyethyl)-phosphorothioate antisense oligonucleotide developed by the Australian company Antisense Therapeutics. The compound is delivered by subcutaneous injection (once or twice a week). Antisense therapy is based on single stranded synthetic oligonucleotides that bind with target mRNA (namely, GHR mRNA) and make it a RNase H substrate. This process leads to a reduction of mRNA translation into protein and, therefore, to a reduced synthesis of GHR. A phase II, randomized, open-label trial, involving 26 acromegaly patients in Europe and Australia, has been completed. Patients were randomized to receive two different drug schedules: 200 mg once or twice a week for 13 weeks. This study showed a significant reduction (27.8%) in IGF-1 levels compared to baseline only in the twice a week arm [45]. IGF-1 levels were still declining at week 14, suggesting that the study was too short to evaluate the maximal effect of this molecule. In fact, the pharmacokinetic profile indicates that the steady state of ATL-1103 is reached approximately after 16 weeks of challenging [45]. Moreover, in order to observe the effect of the antisense oligonucleotide, the GHR already synthetized needs to be degraded (estimated time between 2 to 3 days) [49]. As far as the safety profile, ATL-1103 was well tolerated and only mild to moderate AEs were reported, mostly represented by injection-site reaction. No clinically significant increase in pituitary tumor volume was reported, although a longer follow-up is needed to draw definitive conclusions [45].