Safety and Efficacy of RNAi Therapy for Transthyretin Amyloidosis
Safety and Efficacy of RNAi Therapy for Transthyretin Amyloidosis
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DOI：
10.1056/nejmoa1208760
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发表时间：
2013-08-29
影响因子：
158.5
通讯作者：
Suhr, Ole B.
中科院分区：
文献类型：
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作者：
Coelho, Teresa;Adams, David;Suhr, Ole B.
背景甲状腺素运载蛋白淀粉样变性是由肝细胞来源的甲状腺素运载蛋白淀粉样蛋白在周围神经和心脏的沉积引起的。一种治疗方法介导的RNA干扰（RNAi）可以减少生产transthyretin.MethodsWe确定了一种有效的抗transthyretin小干扰RNA，这是封装在两个不同的第一和第二代制剂的脂质纳米粒子，产生ALN-TTR 01和ALN-TTR 02，分别。在单次给药、安慰剂对照的I期试验中研究了每种制剂，以评估安全性和对甲状腺素运载蛋白水平的影响。我们首先评估ALN-TTR 01（剂量为0.01至1.0毫克每公斤体重）在32例甲状腺素运载蛋白淀粉样变性，然后评估ALN-TTR 02（剂量为0.01至0.5毫克每公斤）在17名健康volunteers.ResultsRapid，剂量依赖性，和持久的降低甲状腺素运载蛋白水平在这两项试验中观察到。在1.0 mg/kg的剂量下，ALN-TTR 01抑制甲状腺素运载蛋白，与安慰剂相比，第7天平均降低38%（P=0.01）;甲状腺素运载蛋白的突变和非突变形式的水平降低到相似的程度。对于ALN-TTR 02，剂量为0.15 - 0.3 mg/kg时，甲状腺素运载蛋白水平的平均降低范围为82.3 - 86.8%，28天时降低56.6 - 67.1%（P
BackgroundTransthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart. A therapeutic approach mediated by RNA interference (RNAi) could reduce the production of transthyretin.MethodsWe identified a potent antitransthyretin small interfering RNA, which was encapsulated in two distinct first- and second-generation formulations of lipid nanoparticles, generating ALN-TTR01 and ALN-TTR02, respectively. Each formulation was studied in a single-dose, placebo-controlled phase 1 trial to assess safety and effect on transthyretin levels. We first evaluated ALN-TTR01 (at doses of 0.01 to 1.0 mg per kilogram of body weight) in 32 patients with transthyretin amyloidosis and then evaluated ALN-TTR02 (at doses of 0.01 to 0.5 mg per kilogram) in 17 healthy volunteers.ResultsRapid, dose-dependent, and durable lowering of transthyretin levels was observed in the two trials. At a dose of 1.0 mg per kilogram, ALN-TTR01 suppressed transthyretin, with a mean reduction at day 7 of 38%, as compared with placebo (P=0.01); levels of mutant and nonmutant forms of transthyretin were lowered to a similar extent. For ALN-TTR02, the mean reductions in transthyretin levels at doses of 0.15 to 0.3 mg per kilogram ranged from 82.3 to 86.8%, with reductions of 56.6 to 67.1% at 28 days (P