title: Suppressing transthyretin production in mice, monkeys and humans using 2nd-Generation antisense oligonucleotides.
abstract: Transthyretin amyloidosis (ATTR amyloidosis) is a rare disease that results from the deposition of misfolded transthyretin (TTR) protein from the plasma into tissues as amyloid fibrils, leading to polyneuropathy and cardiomyopathy. IONIS-TTRRx(ISIS 420915) is a 2nd-Generation 2'-O-(2-methoxyethyl) modified "2'-MOE" antisense oligonucleotide (ASO) that targets the TTR RNA transcript and reduces the levels of the TTR transcript through an RNaseH1 mechanism of action, leading to reductions in both mutant and wild-type TTR protein. The activity of IONIS-TTRRxto decrease TTR protein levels was studied in transgenic mice bearing the Ile84Ser human TTR mutant, in cynomolgus monkeys and in healthy human volunteers. Robust (>80%) reductions of plasma TTR protein were obtained in all three species treated with IONIS-TTRRx, which in mice and monkeys was associated with substantial reductions in hepatic TTR RNA levels. These effects were dose-dependent and lasted for weeks post-dosing. In a Phase 1 healthy volunteer study, treatment with IONIS-TTRRxfor four weeks was well tolerated without any remarkable safety issues. TTR protein reductions up to 96% in plasma were observed. These nonclinical and clinical results support the ongoing Phase 3 development of IONIS-TTRRxin patients with ATTR amyloidosis.
authors.affiliation: a Ionis Pharmaceuticals , Carlsbad , CA , USA and.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Ackermann
authors.affiliation: a Ionis Pharmaceuticals , Carlsbad , CA , USA and.
authors.forename: Shuling
authors.initials: S
authors.lastname: Guo
authors.affiliation: b Department of Pathology and Laboratory Medicine , Indiana University School of Medicine , Indianapolis , IN , USA.
authors.forename: Merrill D
authors.initials: MD
authors.lastname: Benson
authors.affiliation: a Ionis Pharmaceuticals , Carlsbad , CA , USA and.
authors.forename: Sheri
authors.initials: S
authors.lastname: Booten
authors.affiliation: a Ionis Pharmaceuticals , Carlsbad , CA , USA and.
authors.forename: Sue
authors.initials: S
authors.lastname: Freier
authors.affiliation: a Ionis Pharmaceuticals , Carlsbad , CA , USA and.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Hughes
authors.affiliation: a Ionis Pharmaceuticals , Carlsbad , CA , USA and.
authors.forename: Tae-Won
authors.initials: TW
authors.lastname: Kim
authors.affiliation: a Ionis Pharmaceuticals , Carlsbad , CA , USA and.
authors.forename: T
authors.initials: T
authors.lastname: Jesse Kwoh
authors.affiliation: a Ionis Pharmaceuticals , Carlsbad , CA , USA and.
authors.forename: John
authors.initials: J
authors.lastname: Matson
authors.affiliation: a Ionis Pharmaceuticals , Carlsbad , CA , USA and.
authors.forename: Dan
authors.initials: D
authors.lastname: Norris
authors.affiliation: a Ionis Pharmaceuticals , Carlsbad , CA , USA and.
authors.forename: Rosie
authors.initials: R
authors.lastname: Yu
authors.affiliation: a Ionis Pharmaceuticals , Carlsbad , CA , USA and.
authors.forename: Andy
authors.initials: A
authors.lastname: Watt
authors.affiliation: a Ionis Pharmaceuticals , Carlsbad , CA , USA and.
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
mesh_terms: D000293:Adolescent; D000328:Adult; D028227:Amyloid Neuropathies, Familial / Q000628:therapy; D000818:Animals; D004311:Double-Blind Method; D005260:Female; D015870:Gene Expression; D064368:Healthy Volunteers; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011228:Prealbumin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D061251:Primary Cell Culture; D059367:RNA Cleavage; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D016914:Ribonuclease H / Q000378:metabolism*
chemical_list: D016376:Oligonucleotides, Antisense; D011228:Prealbumin; D012333:RNA, Messenger; D016914:Ribonuclease H; C078856:ribonuclease HI
keywords: ATTR; Amyloidosis; FAC; FAP; familial