Liver-directed drugs for transthyretin-mediated amyloidosis.

Publisher: Wiley Country of Publication: United States NLM ID: 9704532 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1529-8027 (Electronic) Linking ISSN: 10859489 NLM ISO Abbreviation: J Peripher Nerv Syst Subsets: MEDLINE

Publication: <2010->: Hoboken, NJ Wiley
Original Publication: New York, NY : Woodland Publications, c1996-

Amyloid Neuropathies, Familial*/drug therapy ; Amyloid Neuropathies, Familial*/genetics ; Prealbumin*/genetics ; Prealbumin*/metabolism; Humans ; Liposomes/therapeutic use ; Liver/metabolism ; RNA, Messenger/genetics ; RNA, Small Interfering/therapeutic use

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. 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. 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 are 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. In summary, ATTR is a progressive disease with various clinical manifestations due to TTR aggregation, deposition, and amyloid formation. Receptor-targeted ligands (eg, GalNAc) and nanoparticle encapsulation (eg, LNPs) are technologies to deliver ASOs, siRNAs, and gene editing tools to hepatocytes, the primary location of TTR synthesis.
(© 2022 The Authors. Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.)

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FS/18/21/33447 United Kingdom BHF_ British Heart Foundation

Keywords: ATTR; CRISPR; RNAi; amyloid; antisense therapy; cardiomyopathy; gene editing; polyneuropathy; siRNA; silencer

0 (Lipid Nanoparticles)
0 (Liposomes)
0 (Prealbumin)
0 (RNA, Messenger)
0 (RNA, Small Interfering)

Amyloidosis, Hereditary, Transthyretin-Related

Date Created: 20221108 Date Completed: 20221206 Latest Revision: 20240320

20240320

PMC10100204

10.1111/jns.12519

36345805