Update on the clinical utility of an RNA interference-based treatment: focus on Patisiran.
Update on the clinical utility of an RNA interference-based treatment: focus on Patisiran.
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DOI：
10.2147/pgpm.s87945
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发表时间：
2017
影响因子：
1.9
通讯作者：
Tüzmen Ş
中科院分区：
文献类型：
--
作者：
Rizk M;Tüzmen Ş
RNA干扰(RNAi)是一种自然存在的转录后基因调控的内源性机制，目前普遍用于基因的功能表征和潜在的疾病治疗策略的开发。基于RNAi的治疗研究，在经过十多年的研究后，终于在开发一种潜在的治疗突变的转甲状腺蛋白(TTR)基因的方法，这种基因会导致TTR蛋白功能失调。这种功能失调的蛋白质会导致TTR淀粉样变性(ATTR)，这是一种遗传性的、渐进性丧失能力的遗传病，通常是致命的。TTR是一种在肝脏中产生的蛋白质，其功能是作为视黄醇结合蛋白和甲状腺激素的载体。这种蛋白质有助于维生素A在人体内的运输。这种蛋白质密码的突变或印刷错误会导致蛋白质的异常折叠。因此，不仅维生素A的运输障碍，而且还会形成称为淀粉样沉积的簇，这会攻击心脏和神经，导致一些患者无条件卧床。ATTR是一种遗传性常染色体显性遗传病，即使父母中只有一人有该基因的单一缺陷等位基因，其后代也有50%的机会遗传。Alnylam制药公司多年来一直致力于RNAi治疗的概念，这导致了围绕小干扰RNA的脂质纳米颗粒的引入。自第一次试验以来，该药物显示出非常积极的结果，缺陷蛋白减少了很大比例。这种药物后来被命名为帕西兰。
RNA interference (RNAi) is a naturally existing endogenous mechanism for post-transcriptional gene regulation, nowadays commonly utilized for functional characterization of genes and development of potential treatment strategies for diseases. RNAi-based studies for therapy, after being examined for over a decade, are finally in the pipeline for developing a potential treatment for the mutated transthyretin (TTR) gene, which gives rise to a dysfunctional TTR protein. This dysfunctional protein causes TTR amyloidosis (ATTR), an inherited, progressively incapacitating, and often fatal genetic disorder. TTR is a protein produced in the liver, and functions as a carrier for retinol-binding protein and also thyroxine. This protein facilitates the transport of vitamin A around the human body. A mutation or misprint in the code of this protein results in an abnormal folding of the protein. Therefore, not only does the transportation of the vitamin A become disabled, but also there will be formation of clusters called amyloid deposits, which attack the heart and the nerves causing some patients to be unconditionally bound to bed. ATTR is a hereditary autosomal dominant disease with a 50% chance of inheritance by offspring, even with just one of the parents having a single defective allele of this gene. Alnylam Pharmaceuticals worked on the concept of RNAi therapy for years, which led to the introduction of lipid nanoparticles encircling small interfering RNAs. The drug showed extremely positive results since the first trial, and a great percentage of defective protein reduction. This drug was later named Patisiran.