Neurology Department, Bicêtre Hospital, INSERM U 1195, CERAMIC, Assistance Publique-Hôpitaux de Paris, University of Paris Saclay, Paris, France.
Cardiology Department, CERAMIC, Bichat Claude Bernard Hospital, University of Paris-Cité, Paris, France.
Blood. 2023 Nov 9;142(19):1600-1612. doi: 10.1182/blood.2023019884.
Hereditary transthyretin amyloidosis (ATTRv) is a rare autosomal dominant adult-onset disorder caused by point mutations in the transthyretin (TTR) gene encoding TTR, also known as prealbumin. ATTRv survival ranges from 3 to 10 years, and peripheral nervous system and heart are usually the 2 main tissues affected, although central nervous system and eye may also be involved. Because the liver is the main TTR protein secretor organ, it has been the main target of treatments developed these last years, including liver transplantation, which has been shown to significantly increase survival in a subset of patients carrying the so-called "early-onset Val30Met" TTR gene mutation. More recently, treatments targeting hepatic TTR RNA have been developed. Hepatic TTR RNA targeting is performed using RNA interference (RNAi) and antisense oligonucleotide (ASO) technologies involving lipid nanoparticle carriers or N-acetylgalactosamine fragments. RNAi and ASO treatments induce an 80% decrease in TTR liver production for a period of 1 to 12 weeks. ASO and RNAi phase 3 trials in patients with TTR-related polyneuropathy have shown a positive impact on neuropathy clinical scores and quality of life end points, and delayed RNAi treatment negatively affects survival. Clinical trials specifically investigating RNAi therapy in TTR cardiomyopathy are underway. Hepatic RNA targeting has revolutionized ATTRv treatment and may allow for the transforming a fatal disease into a treatable disorder. Because retina and choroid plexus secrete limited quantities of TTR protein, both tissues are now seen as the next targets for fully controlling the disease.
遗传性转甲状腺素蛋白淀粉样变性（ATTRv）是一种罕见的常染色体显性遗传的成年发病疾病，由转甲状腺素（TTR）基因编码 TTR（也称为前白蛋白）的点突变引起。ATTRv 的存活时间从 3 到 10 年不等，周围神经系统和心脏通常是受影响的 2 个主要组织，尽管中枢神经系统和眼睛也可能受到影响。由于肝脏是 TTR 蛋白的主要分泌器官，因此它一直是近年来开发的治疗方法的主要目标，包括肝移植，这已被证明可显著增加携带所谓的“早发 Val30Met”TTR 基因突变的患者的生存率。最近，针对肝 TTR RNA 的治疗方法已经开发出来。肝 TTR RNA 靶向是通过使用 RNA 干扰（RNAi）和反义寡核苷酸（ASO）技术实现的，涉及脂质纳米颗粒载体或 N-乙酰半乳糖胺片段。RNAi 和 ASO 治疗可在 1 至 12 周内将 TTR 肝脏产生量降低 80%。在 TTR 相关性多发性神经病患者中进行的 ASO 和 RNAi 第 3 阶段试验表明，对神经病临床评分和生活质量终点有积极影响，延迟 RNAi 治疗会对生存率产生负面影响。正在进行专门针对 TTR 心肌病的 RNAi 治疗临床试验。肝 RNA 靶向治疗彻底改变了 ATTRv 的治疗方法，并可能使这种致命疾病转变为可治疗的疾病。由于视网膜和脉络丛分泌有限数量的 TTR 蛋白，因此这两个组织现在被视为完全控制疾病的下一个目标。
