Evolution of Disease-modifying Therapy for Transthyretin Cardiac Amyloidosis

Published: Jun 27, 2024
Category
Scientific Articles
Key Information
Source
National Library of Medicine
Year
2024
summary/abstract

Transthyretin cardiac amyloidosis (ATTR-CA) represents an inexorably progressive and fatal cardiomyopathy. Increased understanding of the underlying pathogenesis responsible for the misfolding of transthyretin and the subsequent accumulation of amyloid fibrils within the myocardium has led to the development of several disease-modifying therapies that act on different stages of the disease pathway. Tafamidis is the first, and to date remains the only, therapy approved for the treatment of ATTR-CA, which, alongside acoramidis, stabilizes the transthyretin tetramer, preventing disaggregation, misfolding and formation of amyloid fibrils. Gene-silencing agents, such as patisiran, vutrisian and eplontersen, and novel gene-editing therapies, such as NTLA-2001, act to reduce the hepatic synthesis of transthyretin. Anti-amyloid therapies represent another strategy in the treatment of ATTR-CA and are designed to bind amyloid fibril epitopes and stimulate macrophage-mediated removal of amyloid fibrils from the myocardium. Many of these treatments are at an early investigational stage but represent an important area of unmet clinical need and could potentially reverse disease and restore cardiac functions even in patients with advanced disease.

Keywords: Anti-amyloid therapy, cardiac amyloidosis, gene editing therapy, gene silencers, transthyretin cardiac amyloidosis, transthyretin stabilizers

 

Infiltrative cardiomyopathies are a diverse group of cardiac diseases caused by the deposition of abnormal substances within the myocardium and include diseases, such as Fabry disease, sarcoidosis and less common genetic diseases, such as Friedreich’s ataxia and Danon disease. Cardiac amyloidosis is the exemplar infiltrative cardiomyopathy and is characterized by the deposition of misfolded precursor proteins into insoluble, protease-resistant amyloid fibrils, which accumulate in the myocardial extracellular matrix. The deposition of amyloid fibrils disrupt the cardiac structure and function, typically resulting in biventricular wall thickening, stiffening of the myocardium and the development of restrictive physiology and systolic dysfunction. Over 30 different human precursor proteins can form amyloid fibrils, but the majority of cardiac amyloidosis cases result from misfolded transthyretin (transthyretin cardiac amyloidosis [ATTR-CA]) and immunoglobulin light-chain (light-chain amyloidosis [AL]) proteins. Less common, although increasingly recognized, causes of cardiac amyloidosis include apolipoprotein AI amyloidosis and apolipoprotein AIV amyloidosis.–

ATTR-CA represents an important cause of heart failure among older individuals. In the sporadic, non-i nherited, wild-type form, misfolding occurs secondary to a pathological process that is associated with age-related homeostatic mechanisms; this is a condition of older, predominantly male individuals. However, the hereditary form occurs secondary to a single-point mutation in the transthyretin (TTR) gene and often presents with a varying clinical phenotype, often comprising both cardiomyopathy and a length-dependent sensorimotor peripheral polyneuropathy and/or autonomic neuropathy.–

Advances in cardiac imaging, combined with increased awareness among clinicians, have resulted in significantly increased diagnoses in recent years. What was once thought of as a rare disease is increasingly recognized as an important cause of heart failure, especially in older individuals. Furthermore, the variant most commonly associated with ATTR-CA (val122Ile) is present in 3–4% of African Americans, with an estimated 1.5 million individuals in the USA being allele carriers.

Until recently, the mainstay of management for patients with ATTR-CA was supportive therapy using loop diuretics to aid meticulous volume control and treatment of comorbidities, such as anticoagulation in the presence of atrial fibrillation., A recent study of heart failure medications in patients with ATTR-CA demonstrated that mineralocorticoid receptor antagonists and low-dose beta-blockers in patients with a reduced ejection fraction were associated with improved survival; however, neither of these conventional heart failure medications target the specific pathways responsible for ATTR amyloid fibril formation. A deeper understanding of the underlying pathophysiology has resulted in the discovery of multiple, different, disease-specific pharmacotherapies that are either approved for clinical use or at different stages of development. This review will explore the current therapeutic strategies available for patients with ATTR-CA and provide insights into future perspectives.

Transthyretin stabilizers

Current therapeutic strategies are aimed at reducing the formation of ATTR amyloid fibrils and the subsequent deposition within the myocardium to slow disease progression., The discovery of the Thr119Met TTR gene polymorphism, which encodes an amino acid substitution that stabilizes the transthyretin protein, even in the context of known destabilizing pathogenic TTR variants, spurred the development of transthyretin stabilizers. These agents bind to the transthyretin tetramer to prevent the dissociation into amyloidogenic monomers and oligomers that subsequently form pathogenic amyloid fibrils.,

Authors
Adam Ioannou