Kallikrein is the key contact system mediator responsible for the conversion of high-molecular-weight kininogen into the inflammatory vasodilator peptide bradykinin, a process regulated by C1-esterase inhibitor (C1-INH). In hereditary angioedema (HAE), genetic mutations result in deficient or dysfunctional C1-INH and dysregulation of the contact system leading to recurrent, sometimes fatal, angioedema attacks. IONIS-PKKRx is a second-generation 2'-O-(2-methoxyethyl)-modified chimeric antisense oligonucleotide, designed to bind and selectively reduce prekallikrein (PKK) mRNA in the liver. IONIS-PKKRx demonstrated dose-dependent reduction of human prekallikrein hepatic mRNA and plasma protein in transgenic mice and dose- and time-dependent reductions of plasma PKK in Cynomolgus monkeys. Similar dose-dependent reductions of plasma PKK levels were observed in healthy human volunteers accompanied by decreases in bradykinin generation capacity with an acceptable safety and tolerability profile. These results highlight a novel and specific approach to target PKK for the treatment of HAE and other diseases involving contact system activation and overproduction of bradykinin.

中文翻译：

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IONIS-PKKRx是一种前激肽释放酶和缓激肽产生的新型反义抑制剂。

激肽释放酶是关键的接触系统介质，负责将高分子量激肽原转化为炎性血管扩张肽缓激肽，该过程由C1酯酶抑制剂（C1-INH）调节。在遗传性血管性水肿（HAE）中，基因突变导致C1-INH缺乏或功能异常以及接触系统失调，导致复发性血管性水肿发作，甚至是致命的。IONIS-PKKRx是第二代2'-O-（2-甲氧基乙基）修饰的嵌合反义寡核苷酸，旨在结合并选择性降低肝脏中的前激肽释放酶（PKK）mRNA。IONIS-PKKRx证实转基因小鼠中人类前激肽释放酶肝mRNA和血浆蛋白的剂量依赖性降低，食蟹猕猴血浆PKK的剂量依赖性和时间依赖性降低。在健康的人类志愿者中观察到血浆PKK水平的类似剂量依赖性降低，伴随着缓激肽生成能力的降低，并且具有可接受的安全性和耐受性。这些结果突出了一种靶向PKK的新方法和特异性方法，用于治疗HAE和其他涉及接触系统激活和缓激肽产生过高的疾病。