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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 <jats:italic>TTR<\/jats:italic> 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 <jats:italic>TTR<\/jats:italic> mRNA, while a <jats:italic>TTR<\/jats:italic> gene editing tool reduces TTR expression by introducing nonsense mutations into the <jats:italic>TTR<\/jats:italic> gene. Two strategies to facilitate tissue\u2010specific delivery of these nucleic acid\u2010based drugs employ endogenous receptors expressed by hepatocytes. Lipid nanoparticles (LNPs) that recruit apolipoprotein E support low\u2010density lipoprotein receptor\u2010mediated uptake of unconjugated siRNA and are now used for CRISPR gene editing tools. Additionally, conjugating N\u2010acetylgalactosamine (GalNAc) moieties to ASOs or siRNAs facilitates receptor\u2010mediated 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\u2010targeted 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.<\/jats:p>","DOI":"10.1111\/jns.12519","type":"journal-article","created":{"date-parts":[[2022,11,8]],"date-time":"2022-11-08T09:33:30Z","timestamp":1667900010000},"page":"228-237","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Liver\u2010directed drugs for t<scp>ransthyretin\u2010mediated<\/scp> amyloidosis"],"prefix":"10.1111","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1812-8331","authenticated-orcid":false,"suffix":"3rd","given":"Thomas H.","family":"Brannagan","sequence":"first","affiliation":[{"name":"Peripheral Neuropathy Center Columbia University, Vagelos College of Physicians and Surgeons  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John L.","family":"Berk","sequence":"additional","affiliation":[{"name":"Amyloidosis Center Boston University School of Medicine  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian D.","family":"Gillmore","sequence":"additional","affiliation":[{"name":"National Amyloidosis Centre University College London, Royal Free Hospital  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathew S.","family":"Maurer","sequence":"additional","affiliation":[{"name":"Cardiac Amyloidosis Program, Division of Cardiology Columbia College of Physicians and Surgeons  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1rcia","family":"Waddington\u2010Cruz","sequence":"additional","affiliation":[{"name":"National Amyloidosis Referral Center\u2010CEPARM University Hospital Federal University of Rio de Janeiro  Rio de Janeiro Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Fontana","sequence":"additional","affiliation":[{"name":"National Amyloidosis Centre University College London, Royal Free Hospital  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Masri","sequence":"additional","affiliation":[{"name":"Cardiac Amyloidosis Program, Knight Cardiovascular Institute Oregon Health &amp; Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7468-700X","authenticated-orcid":false,"given":"Laura","family":"Obici","sequence":"additional","affiliation":[{"name":"Amyloidosis Research and Treatment Center IRCCS Fondazione Policlinico San Matteo  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Brambatti","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc.  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