Brannagan, Thomas H;
Berk, John L;
Gillmore, Julian D;
Maurer, Mathew S;
Waddington-Cruz, Márcia;
Fontana, Marianna;
Masri, Ahmad;
... Nativi-Nicolau, Jose; + view all
(2022)
Liver Directed Drugs for Transthyretin-Mediated Amyloidosis.
Journal of the Peripheral Nervous System
, 27
(4)
pp. 228-237.
10.1111/jns.12519.
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Abstract
AIM: Transthyretin-mediated amyloidosis (ATTR) is a rare, under-recognized, progressively debilitating, fatal disease caused by the aggregation and extracellular deposition of amyloid transthyretin (TTR) fibrils in multiple organs and tissues throughout the body. TTR is predominantly synthesized by the liver, and normally circulates as a homotetramer, while misfolded monomers aggregate to form amyloid fibrils. One strategy to treat ATTR amyloidosis is to reduce the amount of TTR produced by the liver using drugs that directly target the TTR mRNA or gene. METHODS: This narrative review focuses on how TTR gene silencing tools act to reduce TTR production, describing strategies for improved targeted delivery of these agents to hepatocytes where TTR is preferentially expressed. RESULTS: Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), termed RNA silencers, cause selective degradation of TTR mRNA, while a TTR gene editing tool reduces TTR expression by introducing nonsense mutations into the TTR gene. Two strategies to facilitate tissue-specific delivery of these nucleic acid-based drugs employ endogenous receptors expressed by hepatocytes. Lipid nanoparticles (LNPs) that recruit apolipoprotein E support low density lipoprotein receptor-mediated uptake of unconjugated siRNA and is now used for CRISPR gene editing tools. Additionally, conjugating N-acetylgalactosamine (GalNAc) moieties to ASOs or siRNAs facilitates receptor-mediated uptake by the asialoglycoprotein receptor. CONCLUSION: ATTR is a progressive disease with various clinical manifestations due to TTR aggregation, deposition, and amyloid formation. Receptor-targeted ligands (e.g., GalNAc) and nanoparticle encapsulation (e.g., LNPs) are technologies to deliver ASOs, siRNAs, and gene editing tools to hepatocytes, the primary location of TTR synthesis.
| Type: | Article |
|---|---|
| Title: | Liver Directed Drugs for Transthyretin-Mediated Amyloidosis |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/jns.12519 |
| Publisher version: | https://doi.org/10.1111/jns.12519 |
| Language: | English |
| Additional information: | Copyright © 2022 The Authors. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
| Keywords: | ATTR, CRISPR, Gene editing, RNAi, amyloid, antisense therapy, cardiomyopathy, polyneuropathy, siRNA, silencer |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10159741 |
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