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Liver-directed drugs for transthyretin-mediated amyloidosis.
Brannagan, Thomas H; Berk, John L; Gillmore, Julian D; Maurer, Mathew S; Waddington-Cruz, Márcia; Fontana, Marianna; Masri, Ahmad; Obici, Laura; Brambatti, Michela; Baker, Brenda F; Hannan, Lisa A; Buchele, Gustavo; Viney, Nick J; Coelho, Teresa; Nativi-Nicolau, Jose.
Afiliação
  • Brannagan TH; Peripheral Neuropathy Center, Columbia University, Vagelos College of Physicians and Surgeons, New York, New York, USA.
  • Berk JL; Amyloidosis Center, Boston University School of Medicine, Boston, Massachusetts, USA.
  • Gillmore JD; National Amyloidosis Centre, University College London, Royal Free Hospital, London, UK.
  • Maurer MS; Cardiac Amyloidosis Program, Division of Cardiology, Columbia College of Physicians and Surgeons, New York, New York, USA.
  • Waddington-Cruz M; National Amyloidosis Referral Center-CEPARM, University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
  • Fontana M; National Amyloidosis Centre, University College London, Royal Free Hospital, London, UK.
  • Masri A; Cardiac Amyloidosis Program, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon, USA.
  • Obici L; Amyloidosis Research and Treatment Center, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy.
  • Brambatti M; Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.
  • Baker BF; Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.
  • Hannan LA; Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.
  • Buchele G; Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.
  • Viney NJ; Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.
  • Coelho T; Department of Neurosciences, Centro Hospitalar Universitário do Porto, Porto, Portugal.
  • Nativi-Nicolau J; Division of Heart Failure and Transplant, Mayo Clinic, Jacksonville, Florida, USA.
J Peripher Nerv Syst ; 27(4): 228-237, 2022 12.
Article em En | MEDLINE | ID: mdl-36345805
ABSTRACT
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pré-Albumina / Neuropatias Amiloides Familiares Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pré-Albumina / Neuropatias Amiloides Familiares Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article