National Amyloidosis Centre, Royal Free Hospital, University College London, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK.
BioDrugs. 2023 Mar;37(2):127-142. doi: 10.1007/s40259-023-00577-7. Epub 2023 Feb 16.
Transthyretin (TTR) is a tetrameric protein synthesized primarily by the liver. TTR can misfold into pathogenic ATTR amyloid fibrils that deposit in the nerves and heart, causing a progressive and debilitating polyneuropathy (PN) and life-threatening cardiomyopathy (CM). Therapeutic strategies, which are aimed at reducing ongoing ATTR amyloid fibrillogenesis, include stabilization of the circulating TTR tetramer or reduction of TTR synthesis. Small interfering RNA (siRNA) or antisense oligonucleotide (ASO) drugs are highly effective at disrupting the complementary mRNA and inhibiting TTR synthesis. Since their development, patisiran (siRNA), vutrisiran (siRNA) and inotersen (ASO) have all been licensed for treatment of ATTR-PN, and early data suggest these drugs may have efficacy in treating ATTR-CM. An ongoing phase 3 clinical trial will evaluate the efficacy of eplontersen (ASO) in the treatment of both ATTR-PN and ATTR-CM, and a recent phase 1 trial demonstrated the safety of novel in vivo CRISPR-Cas9 gene-editing therapy in patients with ATTR amyloidosis. Recent results from trials of gene silencer and gene-editing therapies suggest these novel therapeutic agents have the potential to substantially alter the landscape of treatment for ATTR amyloidosis. Their success has already changed the perception of ATTR amyloidosis from a universally progressive and fatal disease to one that is treatable through availability of highly specific and effective disease-modifying therapies. However, important questions remain including long-term safety of these drugs, potential for off-target gene editing, and how best to monitor the cardiac response to treatment.Kindly check and confirm the processed running title.This is correct.
转甲状腺素蛋白（TTR）是一种主要由肝脏合成的四聚体蛋白。TTR 可以错误折叠成致病性的 ATTR 淀粉样纤维，在神经和心脏中沉积，导致进行性和进行性衰弱的多发性神经病（PN）和危及生命的心肌病（CM）。旨在减少持续的 ATTR 淀粉样纤维形成的治疗策略包括稳定循环 TTR 四聚体或减少 TTR 合成。小干扰 RNA（siRNA）或反义寡核苷酸（ASO）药物在破坏互补 mRNA 和抑制 TTR 合成方面非常有效。自开发以来，patisiran（siRNA）、vutrisiran（siRNA）和 inotersen（ASO）都已获得治疗 ATTR-PN 的许可，早期数据表明这些药物可能对治疗 ATTR-CM 有效。一项正在进行的 3 期临床试验将评估 eplontersen（ASO）在治疗 ATTR-PN 和 ATTR-CM 中的疗效，最近的 1 期试验证明了新型体内 CRISPR-Cas9 基因编辑疗法在 ATTR 淀粉样变性患者中的安全性。基因沉默剂和基因编辑疗法试验的最新结果表明，这些新型治疗药物有可能彻底改变 ATTR 淀粉样变性的治疗格局。它们的成功已经改变了人们对 ATTR 淀粉样变性的看法，从一种普遍进行性和致命的疾病转变为可通过使用高度特异性和有效的疾病修饰疗法进行治疗的疾病。然而，仍存在一些重要问题，包括这些药物的长期安全性、潜在的脱靶基因编辑以及如何最好地监测治疗对心脏的反应。请检查并确认处理后的运行标题。这是正确的。
