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Targeted suppression of an amyloidogenic transthyretin with antisense oligonucleotides
Author(s) -
Benson Merrill D.,
KluveBeckerman Barbara,
Zeldenrust Steven R.,
Siesky Angela M.,
Bodenmiller Diane M.,
Showalter Aaron D.,
Sloop Kyle W.
Publication year - 2006
Publication title -
muscle and nerve
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.025
H-Index - 145
eISSN - 1097-4598
pISSN - 0148-639X
DOI - 10.1002/mus.20503
Subject(s) - transthyretin , amyloidosis , amyloid disease , medicine , liver transplantation , amyloid (mycology) , mutation , antisense therapy , transplantation , pathology , endocrinology , disease , oligonucleotide , biology , amyloid fibril , gene , biochemistry , amyloid β , locked nucleic acid
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. Muscle Nerve, 2006