Reducing amyloid formation through TTR gene silencing: patisiran and vutrisiran

Abstract Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure resulting from deposition of misfolded transthyretin (TTR) protein in the myocardial extracellular space. Recent therapeutic advances have transformed the management of this condition, particularly with the development of gene-silencing therapies targeting TTR production by the liver. Two small interfering RNA (siRNA) agents have demonstrated clinical efficacy in phase 3 randomized controlled trials. While patisiran showed functional and biomarker benefits in the APOLLO-B trial, regulatory approval for ATTR-CM was not granted due to concerns regarding clinical meaningfulness of effect size. In contrast, vutrisiran demonstrated significant reductions in all-cause mortality and recurrent cardiovascular events in the HELIOS-B trial, along with improvements in functional capacity and quality of life, leading to regulatory approval. Gene silencing represents a major paradigm shift in ATTR-CM, offering substantial prognostic benefit without evidence of significant short- to mid-term safety concerns related to TTR depletion. Ongoing and future studies will clarify the role of combination strategies and optimal timing of therapy initiation in earlier disease stages.