Keller Daria M, Straburzyńska-Migaj Ewa, Lesiak Maciej
1st Department of Cardiology, Poznan University of Medical Sciences, Poznań, Poland.
Department of Pulmonology, Allergology and Pulmonological Oncology, Poznan University of Medical Sciences, Poznań, Poland.
Kardiol Pol. 2025;83(2):121-137. doi: 10.33963/v.phj.104054. Epub 2025 Jan 7.
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and challenging disease characterized by deposition of misfolded transthyretin (TTR) protein in the myocardial interstitium. Until recently, treatment options for ATTR-CM were limited, with tafamidis emerging as the primary therapeutic agent targeting the stabilization of TTR tetramers to prevent amyloid fibril formation. However, advancements in understanding the underlying mechanisms of ATTR-CM have led to developing novel therapeutic strategies to address various aspects of the disease process. This review explores current therapeutic options for treating ATTR-CM. It encompasses strategies ranging from inhibiting TTR synthesis using RNA silencing methods, such as small interfering RNA (siRNA; e.g., the HELIOS-B trial with vutrisiran), antisense oligonucleotides (ASO; e.g., the CARDIO-TTRansform trial with eplontersen), and gene-editing technologies such as CRISPR/Cas9 (e.g., the MAGNITUDE trial with NTLA-2001). Additionally, it explores TTR stabilization approaches beyond tafamidis, such as next-generation acoramidis, which showed success in the ATTRibute-CM trial. It also examines therapies promoting TTR degradation and removal, which includes the use of monoclonal antibodies (e.g., DepleTTR-CM with ALXN2220) and other compounds, such as doxycycline or epigallocatechin-3-gallate (a green tea component), which, despite long-standing recognition, remain underexplored. Novel approaches, such as seeding inhibitors and molecular tweezers, which aim to inhibit TTR fibril formation, are also discussed as potential future management strategies. The review further highlights the role of ongoing clinical trials in evaluating the efficacy and safety of these innovative therapies, emphasizing their potential to expand treatment options and improve outcomes for patients with ATTR-CM. Advancements in supportive therapies are also discussed to offer a comprehensive overview of the evolving therapeutic landscape.
转甲状腺素蛋白淀粉样变心肌病（ATTR-CM）是一种进行性且具有挑战性的疾病，其特征是错误折叠的转甲状腺素蛋白（TTR）在心肌间质中沉积。直到最近，ATTR-CM的治疗选择仍然有限，他法米地成为主要的治疗药物，其作用是稳定TTR四聚体以防止淀粉样纤维形成。然而，对ATTR-CM潜在机制认识的进展促使人们开发新的治疗策略来应对疾病过程的各个方面。本综述探讨了目前治疗ATTR-CM的选择。它涵盖了多种策略，从使用RNA沉默方法抑制TTR合成，如小干扰RNA（siRNA；例如使用vutrisiran的HELIOS-B试验）、反义寡核苷酸（ASO；例如使用依洛特森的CARDIO-TTRansform试验），到基因编辑技术如CRISPR/Cas9（例如使用NTLA-2001的MAGNITUDE试验）。此外，它还探讨了除他法米地之外的TTR稳定化方法，如下一代阿考米地，其在ATTRibute-CM试验中取得了成功。它还研究了促进TTR降解和清除的疗法，包括使用单克隆抗体（例如使用ALXN2220的DepleTTR-CM）以及其他化合物，如多西环素或表没食子儿茶素-3-没食子酸酯（一种绿茶成分），尽管这些方法早已被认识到，但仍未得到充分研究。旨在抑制TTR纤维形成的新方法，如种子抑制剂和分子镊子，也作为潜在的未来管理策略进行了讨论。该综述进一步强调了正在进行的临床试验在评估这些创新疗法的疗效和安全性方面的作用，强调了它们扩大治疗选择和改善ATTR-CM患者预后的潜力。还讨论了支持性疗法的进展，以全面概述不断演变的治疗格局。
