Suppressing transthyretin production in mice, monkeys and humans using 2nd-Generation antisense oligonucleotides

Elizabeth J. Ackermann, Shuling Guo, Merrill Benson, Sheri Booten, Sue Freier, Steven G. Hughes, Tae Won Kim, T. Jesse Kwoh, John Matson, Dan Norris, Rosie Yu, Andy Watt, Brett P. Monia

Research output: Contribution to journalArticle

55 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
StateAccepted/In press - Jun 17 2016



  • Amyloidosis
  • ATTR
  • FAC
  • familial
  • FAP

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Ackermann, E. J., Guo, S., Benson, M., Booten, S., Freier, S., Hughes, S. G., Kim, T. W., Jesse Kwoh, T., Matson, J., Norris, D., Yu, R., Watt, A., & Monia, B. P. (Accepted/In press). Suppressing transthyretin production in mice, monkeys and humans using 2nd-Generation antisense oligonucleotides. Amyloid, 1-10.