Evaluation of tafamidis as first-line therapeutic agent for transthyretin familial amyloidotic polyneuropathy.

Degenerative Neurological and Neuromuscular Disease Pub Date : 2012-10-19 eCollection Date: 2012-01-01 DOI:10.2147/DNND.S24624
Joel N Buxbaum
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引用次数: 2

Abstract

Almost 100 mutations in the human transthyretin (TTR) gene cause the autosomal dominant disorders of familial amyloidotic polyneuropathy (FAP) and familial amyloidotic cardiomyopathy. While these have been clinically classified as separate disorders, the peripheral and autonomic nervous systems and the heart are frequently involved in the same patient. Deposition of amyloid derived from a kinetically or thermodynamically unstable mutant TTR precursor produces an ascending sensorimotor polyneuropathy with marked autonomic involvement. Since 1990, treatment has been liver transplantation from a donor carrying two wild-type TTR genes, providing a crude form of gene therapy. Multiple studies have shown that small molecules fitting in the T4-binding pocket of TTR can stabilize the molecule, reducing its capacity to release the fibril precursor. Tafamidis is the first molecule to be tested in a placebo-controlled trial in patients with TTR-associated FAP. While the trial did not achieve its primary endpoints, it did stabilize TTR in vivo and had a favorable effect on some aspects of disease progression, particularly when administered early in the course. It may represent an alternative to liver transplantation, particularly in patients with early disease related to the V30M mutation. Longer-term studies are required to determine whether it represents a stabilizing or remittive form of treatment.

他法非地作为经甲状腺素家族性淀粉样变性多发性神经病一线治疗药物的评价。
近100个人甲状腺转蛋白(TTR)基因突变导致家族性淀粉样变性多神经病变(FAP)和家族性淀粉样变性心肌病的常染色体显性遗传病。虽然这些在临床上被分类为不同的疾病,但周围神经系统和自主神经系统以及心脏经常发生在同一患者身上。来源于动力或热力学不稳定的TTR前体突变体的淀粉样蛋白沉积产生上升的感觉运动多发性神经病,伴有明显的自主神经受累。自1990年以来,治疗一直是来自携带两个野生型TTR基因的供体的肝移植,提供了一种原始的基因治疗形式。多项研究表明,适合TTR的t4结合口袋的小分子可以稳定分子,降低其释放原纤维前体的能力。Tafamidis是第一个在trr相关FAP患者中进行安慰剂对照试验的分子。虽然该试验没有达到其主要终点,但它确实稳定了体内的TTR,并对疾病进展的某些方面产生了有利的影响,特别是在病程早期给药时。它可能是肝移植的一种替代方法,特别是在与V30M突变相关的早期疾病患者中。需要更长期的研究来确定它是否代表一种稳定或缓解的治疗形式。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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