Adams David, Sekijima Yoshiki, Conceição Isabel, Waddington-Cruz Marcia, Polydefkis Michael, Echaniz-Laguna Andoni, Reilly Mary M
Department of Neurology, Bicêtre Centre Hospitalo Universitaire, AP-HP, INSERM U 1195, University Paris Saclay, Le Kremlin Bicetre, France.
Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan.
Lancet Neurol. 2023 Nov;22(11):1061-1074. doi: 10.1016/S1474-4422(23)00334-4.
Hereditary transthyretin (TTR) amyloid polyneuropathy is an autosomal dominant life-threatening disorder. TTR is produced mainly by the liver but also by the choroid plexus and retinal pigment epithelium. Detailed clinical characterisation, identification of clinical red flags for misdiagnosis, and use of biomarkers enable early diagnosis and treatment. In addition to liver transplantation and TTR stabilisers, three other disease-modifying therapies have regulatory approval: one antisense oligonucleotide (inotersen) and two small interfering RNAs (siRNAs; patisiran and vutrisiran). The siRNAs have been shown to stop progression of neuropathy and improve patients' quality of life. As none of the disease-modifying therapies can cross the blood-brain barrier, TTR deposition in the CNS, which can cause stroke and cognitive impairment, remains an important unaddressed issue. CRISPR-Cas9-based one-time TTR editing therapy is being investigated in a phase 1 clinical study. Identification of the earliest stages of pathogenesis in TTR variant carriers is a major challenge that needs addressing for optimal management.
遗传性转甲状腺素蛋白（TTR）淀粉样多神经病是一种常染色体显性遗传的危及生命的疾病。TTR主要由肝脏产生，但脉络丛和视网膜色素上皮也可产生。详细的临床特征描述、识别误诊的临床警示信号以及生物标志物的使用有助于早期诊断和治疗。除肝移植和TTR稳定剂外，还有另外三种疾病修正疗法已获得监管批准：一种反义寡核苷酸（inotersen）和两种小干扰RNA（siRNA；patisiran和vutrisiran）。这些siRNA已被证明可阻止神经病变进展并改善患者生活质量。由于没有一种疾病修正疗法能够穿过血脑屏障，TTR在中枢神经系统中的沉积（可导致中风和认知障碍）仍然是一个重要的未解决问题。基于CRISPR-Cas9的一次性TTR编辑疗法正在一项1期临床研究中进行调查。识别TTR变异携带者发病机制的最早阶段是最佳管理中需要解决的一项重大挑战。
