Suppressing transthyretin production in mice, monkeys and humans using 2nd-Generation antisense oligonucleotides
- 29 June 2016
- journal article
- research article
- Published by Taylor & Francis Ltd in Amyloid
- Vol. 23 (3), 148-157
- https://doi.org/10.1080/13506129.2016.1191458
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-TTRRx to 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-TTRRx for 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-TTRRx in patients with ATTR amyloidosis.Keywords
This publication has 27 references indexed in Scilit:
- Repurposing Diflunisal for Familial Amyloid PolyneuropathyJAMA, 2013
- Tafamidis for transthyretin familial amyloid polyneuropathyNeurology, 2012
- RNA Targeting Therapeutics: Molecular Mechanisms of Antisense Oligonucleotides as a Therapeutic PlatformAnnual Review of Pharmacology and Toxicology, 2010
- Effect of dose and plasma concentration on liver uptake and pharmacologic activity of a 2′-methoxyethyl modified chimeric antisense oligonucleotide targeting PTENBiochemical Pharmacology, 2009
- Targeted suppression of an amyloidogenic transthyretin with antisense oligonucleotidesMuscle & Nerve, 2006
- Tissue damage in the amyloidoses: Transthyretin monomers and nonnative oligomers are the major cytotoxic species in tissue cultureProceedings of the National Academy of Sciences of the United States of America, 2004
- Efficient Reduction of Target RNAs by Small Interfering RNA and RNase H-dependent Antisense AgentsOnline Journal of Public Health Informatics, 2003
- Tabulation of human transthyretin (TTR) variants, 2003Amyloid, 2003
- The Systemic AmyloidosesThe New England Journal of Medicine, 1997
- Transthyretin amyloidosisAmyloid, 1996