eprintid: 10165469 rev_number: 9 eprint_status: archive userid: 699 dir: disk0/10/16/54/69 datestamp: 2023-02-23 14:11:45 lastmod: 2024-10-30 17:28:54 status_changed: 2023-02-23 14:11:45 type: article metadata_visibility: show sword_depositor: 699 creators_name: Ioannou, Adam creators_name: Fontana, Marianna creators_name: Gillmore, Julian D title: RNA Targeting and Gene Editing Strategies for Transthyretin Amyloidosis ispublished: inpress subjects: RFH divisions: UCL divisions: B02 divisions: C10 divisions: D17 divisions: G90 note: This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/. abstract: Transthyretin (TTR) is a tetrameric protein synthesized primarily by the liver. TTR can misfold into pathogenic ATTR amyloid fibrils that deposit in the nerves and heart, causing a progressive and debilitating polyneuropathy (PN) and life-threatening cardiomyopathy (CM). Therapeutic strategies, which are aimed at reducing ongoing ATTR amyloid fibrillogenesis, include stabilization of the circulating TTR tetramer or reduction of TTR synthesis. Small interfering RNA (siRNA) or antisense oligonucleotide (ASO) drugs are highly effective at disrupting the complementary mRNA and inhibiting TTR synthesis. Since their development, patisiran (siRNA), vutrisiran (siRNA) and inotersen (ASO) have all been licensed for treatment of ATTR-PN, and early data suggest these drugs may have efficacy in treating ATTR-CM. An ongoing phase 3 clinical trial will evaluate the efficacy of eplontersen (ASO) in the treatment of both ATTR-PN and ATTR-CM, and a recent phase 1 trial demonstrated the safety of novel in vivo CRISPR-Cas9 gene-editing therapy in patients with ATTR amyloidosis. Recent results from trials of gene silencer and gene-editing therapies suggest these novel therapeutic agents have the potential to substantially alter the landscape of treatment for ATTR amyloidosis. Their success has already changed the perception of ATTR amyloidosis from a universally progressive and fatal disease to one that is treatable through availability of highly specific and effective disease-modifying therapies. However, important questions remain including long-term safety of these drugs, potential for off-target gene editing, and how best to monitor the cardiac response to treatment.Kindly check and confirm the processed running title.This is correct. date: 2023-02-16 date_type: published publisher: Springer Science and Business Media LLC official_url: https://doi.org/10.1007/s40259-023-00577-7 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 2006382 doi: 10.1007/s40259-023-00577-7 medium: Print-Electronic pii: 10.1007/s40259-023-00577-7 lyricists_name: Gillmore, Julian lyricists_id: JGILL78 actors_name: Flynn, Bernadette actors_id: BFFLY94 actors_role: owner full_text_status: public publication: BioDrugs event_location: New Zealand citation: Ioannou, Adam; Fontana, Marianna; Gillmore, Julian D; (2023) RNA Targeting and Gene Editing Strategies for Transthyretin Amyloidosis. BioDrugs 10.1007/s40259-023-00577-7 <https://doi.org/10.1007/s40259-023-00577-7>. (In press). Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10165469/1/s40259-023-00577-7.pdf