AUTHOR=Williams Marcus A. C. , Shankar Bairavi , Vaishnav Joban , Ranek Mark J. TITLE=Current and potential therapeutic strategies for transthyretin cardiac amyloidosis JOURNAL=Frontiers in Drug Discovery VOLUME=2 YEAR=2022 URL=https://www.frontiersin.org/journals/drug-discovery/articles/10.3389/fddsv.2022.1015545 DOI=10.3389/fddsv.2022.1015545 ISSN=2674-0338 ABSTRACT=

Cardiac amyloidosis is a progressive disorder caused by the deposition of amyloid, abnormal proteins that aggregate to form insoluble plaques in the myocardium resulting in restrictive cardiomyopathy. The two most common subtypes of cardiac amyloidosis are immunoglobulin light chain (AL) and transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM). ATTR-CM can further be subdivided into two main categories, wild-type or hereditary TTR. TTR is a homotetrameric protein complex that is synthesized in the liver and is secreted into the circulation for retinol and vitamin A transfer. Genetic mutations in the TTR gene can disrupt the thermodynamic stability of the homotetrameric complex causing dissociation into monomers that, when taken up by the myocardium, will aggregate to form insoluble fibers. Though the mechanism of wild-type TTR is not fully elucidated, it is thought to be an age-related process. Myocardial uptake and aggregation of TTR monomeric subunits result in cytotoxicity, impaired cardiac function, and eventually heart failure. Historically, ATTR-CM had a poor prognosis, with no therapeutics available to specifically target ATTR-CM and treatment focused on managing symptoms and disease-related complications. In 2019, the FDA approved the first-in-class TTR stabilizer for ATTR-CM, which has led to improved outcomes. In recent years, several promising novel therapies have emerged which aim to target various points of the ATTR-CM amyloidogenic cascade. In this review, we discuss the mechanistic underpinnings of ATTR-CM, review current FDA-approved strategies for treatment, and highlight ongoing research efforts as potential therapeutic options in the future.