Emerging, novel gene-modulating therapies for transthyretin amyloid cardiomyopathy.

Abstract

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, life-threatening disease caused by the pathological deposition of misfolded transthyretin (TTR) protein in the myocardium, leading to restrictive cardiomyopathy and heart failure. While TTR stabilizers such as tafamidis and acoramidis are the only FDA-approved treatments, novel gene-modulating therapies are emerging as transformative approaches. Small interfering RNA (siRNA) and antisense oligonucleotide (ASO) therapies effectively reduce TTR production and have demonstrated promising clinical outcomes, though their use in cardiac amyloidosis remains investigational. CRISPR-Cas9 therapies represent a paradigm shift, offering a potential one-time treatment by permanently silencing the TTR gene. Recent clinical trials have shown significant TTR reduction and stabilization of disease biomarkers, although long-term safety and efficacy require further evaluation. Despite the lack of direct comparisons among these modalities, their emergence highlights a promising future for ATTR-CM management. This review discusses the pathogenesis of ATTR-CM, mechanisms of novel gene-modulating therapies, clinical evidence, challenges, and the future outlook for advancing treatment options.