Clinical development of an antisense therapy for the treatment of transthyretin-associated polyneuropathy
Clinical development of an antisense therapy for the treatment of transthyretin-associated polyneuropathy
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DOI：
10.3109/13506129.2012.673140
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发表时间：
2012-06-01
影响因子：
5.5
通讯作者：
Monia, Brett P.
中科院分区：
文献类型：
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作者：
Ackermann, Elizabeth J.;Guo, Shuling;Monia, Brett P.
甲状腺素运载蛋白（TTR）相关性淀粉样变性是一种晚发型常染色体显性遗传病。在TTR中已经鉴定了超过100种淀粉样蛋白突变，其使TTR四聚体不稳定，从而诱导组织如心脏和外周神经中淀粉样蛋白原纤维的形成。这种疾病主要影响周围神经，引起家族性淀粉样多发性神经病（FAP）或心脏，引起家族性淀粉样心肌病（FAC）。循环TTR主要由肝脏产生，并且FAP的唯一广泛可用的临床治疗是原位肝移植（奥尔特），而目前不存在FAC的治疗。利用第二代反义技术，我们鉴定了靶向TTR的反义寡核苷酸（阿索）ISIS-TTRRx，用于治疗TTR相关淀粉样变性。当在人TTR转基因小鼠模型（hTTR Ile 84 Ser）中测试时，ISIS-TTRRx在mRNA和蛋白质水平均显示人TTR的剂量依赖性降低（高达>80%）。在食蟹猴中，ISIS-TTRRx处理产生血浆TTR水平的时间依赖性降低。在猴中治疗12周后，肝脏TTR mRNA和血浆TTR蛋白水平降低了约80%。正如预期的那样，用ISIS-TTRRx治疗也产生了与TTR水平降低相关的血浆RBP 4水平的显著降低。ISIS-TTRRx治疗在啮齿动物和猴中耐受良好，并产生与使用该化学平台的先前经验一致的PK/PD特征。ISIS-TTRRx目前正在正常健康志愿者中进行I期临床试验，并将提供该试验的中期结果。
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 similar to 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.