Clinical development of an antisense therapy for the treatment of transthyretin-associated polyneuropathy

Elizabeth J. Ackermann, Shuling Guo, Sheri Booten, Luis Alvarado, Merrill Benson, Steve Hughes, Brett P. Monia

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

Transthyretin (TTR)-associated amyloidosis is a late-onset autosomal-dominant genetic disease. Over 100 amyloidogenic mutations have been identified in TTR which destabilize the TTR tetramer thereby inducing the formation of amyloid fibrils in tissues such as the heart and peripheral nerves. This disease mainly affects peripheral nerves, causing familial amyloid polyneuropathy (FAP) or heart, causing familial amyloid cardiomyopathy (FAC). Circulating TTR is predominantly produced by liver, and the only widely available clinical treatment for FAP is orthotopic liver transplantation (OLT), whereas no treatment currently exists for FAC. Using second-generation antisense technology, we identified an antisense oligonucleotide (ASO) targeting TTR, ISIS-TTRRx, for the treatment of TTR-associated amyloidosis. When tested in a human TTR transgenic mouse model (hTTR Ile84Ser), ISIS-TTRRx showed a dose-dependent reduction of human TTR (up to >80%) at both the mRNA and protein levels. In cynomolgus monkeys, ISIS-TTRRx treatment produced a time-dependent reduction in plasma TTR levels. After 12 weeks of treatment in monkey, liver TTR mRNA and plasma TTR protein levels were reduced by ~80%. As expected, treatment with ISIS-TTRRx also produced a significant decrease in plasma RBP4 levels that correlated with reductions in TTR levels. ISIS-TTRRx treatment was well tolerated in both rodents and monkeys and produced a PK/PD profile consistent with prior experiences using this chemistry platform. ISIS-TTRRx is currently under evaluation in a Phase 1 clinical trial in normal healthy volunteers, and interim results of this trial will be presented.

Original languageEnglish
Pages (from-to)43-44
Number of pages2
JournalAmyloid
Volume19
Issue numberSUPPL. 1
DOIs
StatePublished - Jun 2012

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Prealbumin
Polyneuropathies
Familial Amyloid Neuropathies
Amyloid
Therapeutics
Cardiomyopathies
Peripheral Nerves
Haplorhini
Healthy Volunteers
Messenger RNA
Clinical Trials, Phase I
Inborn Genetic Diseases
Macaca fascicularis
Antisense Oligonucleotides
Liver
Liver Transplantation
Transgenic Mice
Blood Proteins
Rodentia
Technology

Keywords

  • Amyloidosis
  • Antisense
  • Transthyretin

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Ackermann, E. J., Guo, S., Booten, S., Alvarado, L., Benson, M., Hughes, S., & Monia, B. P. (2012). Clinical development of an antisense therapy for the treatment of transthyretin-associated polyneuropathy. Amyloid, 19(SUPPL. 1), 43-44. https://doi.org/10.3109/13506129.2012.673140

Clinical development of an antisense therapy for the treatment of transthyretin-associated polyneuropathy. / Ackermann, Elizabeth J.; Guo, Shuling; Booten, Sheri; Alvarado, Luis; Benson, Merrill; Hughes, Steve; Monia, Brett P.

In: Amyloid, Vol. 19, No. SUPPL. 1, 06.2012, p. 43-44.

Research output: Contribution to journalArticle

Ackermann, EJ, Guo, S, Booten, S, Alvarado, L, Benson, M, Hughes, S & Monia, BP 2012, 'Clinical development of an antisense therapy for the treatment of transthyretin-associated polyneuropathy', Amyloid, vol. 19, no. SUPPL. 1, pp. 43-44. https://doi.org/10.3109/13506129.2012.673140
Ackermann, Elizabeth J. ; Guo, Shuling ; Booten, Sheri ; Alvarado, Luis ; Benson, Merrill ; Hughes, Steve ; Monia, Brett P. / Clinical development of an antisense therapy for the treatment of transthyretin-associated polyneuropathy. In: Amyloid. 2012 ; Vol. 19, No. SUPPL. 1. pp. 43-44.
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