Targeted suppression of an amyloidogenic transthyretin with antisense oligonucleotides

Muscle Nerve. 2006 May;33(5):609-18. doi: 10.1002/mus.20503.


Transthyretin (TTR) amyloidosis, the most common form of hereditary systemic amyloidosis, is characterized clinically by adult-onset axonal neuropathy and restrictive cardiomyopathy. More than 85 mutations in transthyretin have been found to cause this hereditary disease. Since essentially all circulating TTR is of hepatic origin, orthotopic liver transplantation has been used as the only specific form of therapy. Unfortunately, in many patients amyloid deposition continues after orthotopic liver transplantation, indicating that mutant TTR is no longer required for progression of the disease after tissue deposits have been initiated. As a first step toward medical treatment of this disease, we have employed antisense oligonucleotides (ASOs) to inhibit hepatic expression of TTR. A transgenic mouse model carrying the human TTR Ile84Ser mutation was created and shown to express high levels of human mutant transthyretin. TTR ASOs suppressed hepatic TTR mRNA levels and serum TTR levels by as much as 80%. Suppression of hepatic synthesis of transthyretin may offer a medical treatment for transthyretin systemic amyloidosis.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alanine Transaminase / blood
  • Amyloidosis, Familial / blood
  • Amyloidosis, Familial / drug therapy*
  • Amyloidosis, Familial / genetics*
  • Animals
  • Aspartate Aminotransferases / blood
  • Carcinoma, Hepatocellular / pathology
  • Cells, Cultured
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Gene Expression / drug effects
  • Gene Silencing*
  • Humans
  • Immunohistochemistry / methods
  • Isoleucine / genetics
  • Liver / drug effects
  • Liver / enzymology
  • Mice
  • Mice, Transgenic
  • Mutation / physiology
  • Oligonucleotides, Antisense / therapeutic use*
  • Prealbumin / antagonists & inhibitors*
  • Prealbumin / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Serine / genetics
  • Time Factors


  • Oligonucleotides, Antisense
  • Prealbumin
  • RNA, Messenger
  • Isoleucine
  • Serine
  • Aspartate Aminotransferases
  • Alanine Transaminase