Targeted suppression of an amyloidogenic transthyretin with antisense oligonucleotides
Targeted suppression of an amyloidogenic transthyretin with antisense oligonucleotides
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DOI：
10.1002/mus.20503
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发表时间：
2006-05-01
期刊：
影响因子：
3.4
通讯作者：
Sloop, KW
中科院分区：
文献类型：
--
作者：
Benson, MD;Kluve-Beckerman, B;Sloop, KW
转甲状腺素（TTR）淀粉样变是遗传性系统性淀粉样变最常见的形式，临床表现为成人发病的轴突神经病变和限制性心肌病。已发现超过85种甲状腺转甲素突变可导致这种遗传性疾病。由于基本上所有循环的TTR都来自肝脏，原位肝移植已被用作唯一的特定治疗形式。不幸的是，在许多患者中，原位肝移植后淀粉样蛋白沉积仍在继续，这表明在组织沉积开始后，突变的TTR不再是疾病进展所需要的。作为医学治疗这种疾病的第一步，我们使用反义寡核苷酸（ASOs）来抑制肝脏中TTR的表达。建立了携带人类TTR Ile84Ser突变的转基因小鼠模型，并显示其表达高水平的人类突变体转甲状腺素。TTR ASOs可抑制肝脏TTR mRNA水平和血清TTR水平高达80%。抑制转甲状腺素的肝脏合成可能为转甲状腺素系统性淀粉样变性提供一种医学治疗方法。
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.