title: Preclinical evaluation of RNAi as a treatment for transthyretin-mediated amyloidosis.
abstract: ATTR amyloidosis is a systemic, debilitating and fatal disease caused by transthyretin (TTR) amyloid accumulation. RNA interference (RNAi) is a clinically validated technology that may be a promising approach to the treatment of ATTR amyloidosis. The vast majority of TTR, the soluble precursor of TTR amyloid, is expressed and synthesized in the liver. RNAi technology enables robust hepatic gene silencing, the goal of which would be to reduce systemic levels of TTR and mitigate many of the clinical manifestations of ATTR that arise from hepatic TTR expression. To test this hypothesis, TTR-targeting siRNAs were evaluated in a murine model of hereditary ATTR amyloidosis. RNAi-mediated silencing of hepatic TTR expression inhibited TTR deposition and facilitated regression of existing TTR deposits in pathologically relevant tissues. Further, the extent of deposit regression correlated with the level of RNAi-mediated knockdown. In comparison to the TTR stabilizer, tafamidis, RNAi-mediated TTR knockdown led to greater regression of TTR deposits across a broader range of affected tissues. Together, the data presented herein support the therapeutic hypothesis behind TTR lowering and highlight the potential of RNAi in the treatment of patients afflicted with ATTR amyloidosis.
authors.affiliation: a Alnylam Pharmaceuticals , Cambridge , MA , USA .
authors.forename: James S
authors.initials: JS
authors.lastname: Butler
authors.affiliation: a Alnylam Pharmaceuticals , Cambridge , MA , USA .
authors.forename: Amy
authors.initials: A
authors.lastname: Chan
authors.affiliation: b Instituto de Investigação e Inovação em Saúde, Universidade do Porto , Porto , Portugal .|c Molecular Neurobiology, IBMC - Institute for Molecular and Cell Biology Porto , Porto , Portugal.
authors.forename: Susete
authors.initials: S
authors.lastname: Costelha
authors.affiliation: a Alnylam Pharmaceuticals , Cambridge , MA , USA .
authors.forename: Shannon
authors.initials: S
authors.lastname: Fishman
authors.affiliation: a Alnylam Pharmaceuticals , Cambridge , MA , USA .
authors.forename: Jennifer L S
authors.initials: JL
authors.lastname: Willoughby
authors.affiliation: a Alnylam Pharmaceuticals , Cambridge , MA , USA .
authors.forename: Todd D
authors.initials: TD
authors.lastname: Borland
authors.affiliation: a Alnylam Pharmaceuticals , Cambridge , MA , USA .
authors.forename: Stuart
authors.initials: S
authors.lastname: Milstein
authors.affiliation: a Alnylam Pharmaceuticals , Cambridge , MA , USA .
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Foster
authors.affiliation: b Instituto de Investigação e Inovação em Saúde, Universidade do Porto , Porto , Portugal .|c Molecular Neurobiology, IBMC - Institute for Molecular and Cell Biology Porto , Porto , Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Gonçalves
authors.affiliation: a Alnylam Pharmaceuticals , Cambridge , MA , USA .
authors.forename: Qingmin
authors.initials: Q
authors.lastname: Chen
authors.affiliation: a Alnylam Pharmaceuticals , Cambridge , MA , USA .
authors.forename: June
authors.initials: J
authors.lastname: Qin
authors.affiliation: a Alnylam Pharmaceuticals , Cambridge , MA , USA .
authors.forename: Brian R
authors.initials: BR
authors.lastname: Bettencourt
authors.affiliation: a Alnylam Pharmaceuticals , Cambridge , MA , USA .
authors.forename: Dinah W
authors.initials: DW
authors.lastname: Sah
authors.affiliation: a Alnylam Pharmaceuticals , Cambridge , MA , USA .
authors.forename: Rene
authors.initials: R
authors.lastname: Alvarez
authors.affiliation: a Alnylam Pharmaceuticals , Cambridge , MA , USA .
authors.forename: Kallanthottathil G
authors.initials: KG
authors.lastname: Rajeev
authors.affiliation: a Alnylam Pharmaceuticals , Cambridge , MA , USA .
authors.forename: Muthiah
authors.initials: M
authors.lastname: Manoharan
authors.affiliation: a Alnylam Pharmaceuticals , Cambridge , MA , USA .
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzgerald
authors.affiliation: a Alnylam Pharmaceuticals , Cambridge , MA , USA .
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Meyers
authors.affiliation: a Alnylam Pharmaceuticals , Cambridge , MA , USA .
authors.forename: Saraswathy V
authors.initials: SV
authors.lastname: Nochur
authors.affiliation: b Instituto de Investigação e Inovação em Saúde, Universidade do Porto , Porto , Portugal .|c Molecular Neurobiology, IBMC - Institute for Molecular and Cell Biology Porto , Porto , Portugal.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Saraiva
authors.affiliation: a Alnylam Pharmaceuticals , Cambridge , MA , USA .
authors.forename: Tracy S
authors.initials: TS
authors.lastname: Zimmermann
mesh_terms: D028227:Amyloid Neuropathies, Familial / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001583:Benzoxazoles / Q000494:pharmacology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D015870:Gene Expression; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011228:Prealbumin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001583:Benzoxazoles; D011228:Prealbumin; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C000606954:patisiran; C547076:tafamidis
keywords: GalNAc; gene silencing; lipid nanoparticle; siRNA; therapeutic