Transthyretin Amyloidosis: From Mechanisms to Treatment

Transthyretin amyloidosis (ATTR) is a progressive systemic disorder driven by the misfolding of transthyretin (TTR) proteins and their deposition as amyloid fibrils. It manifests as hereditary ATTR (ATTRv), caused by pathogenic variants, and wild-type ATTR (ATTRwt), linked primarily to aging. These deposits preferentially affect the myocardium and peripheral nerves, producing severe cardiomyopathy and polyneuropathy. The amyloidogenic cascade is initiated by the dissociation of TTR tetramers into misfolded monomers that aggregate into insoluble fibrils. Historically, treatment was limited to supportive care or organ transplantation; however, it has been transformed by TTR stabilizers, RNA interference (RNAi) agents, and antisense oligonucleotides (ASOs). More recently, CRISPR-Cas9 genome editing has emerged as a potential single-dose strategy for durable TTR suppression. In parallel, anti-fibril therapies, including amyloid-depleting monoclonal antibodies designed to clear existing tissue deposits, are being developed as a complementary disease-modifying strategy. This review delineates the molecular mechanisms of amyloidogenesis and evaluates current clinical management strategies. Recent advances in noninvasive diagnostics and targeted molecular therapies, enabled by precision medicine, have markedly improved disease management and clinical outcomes.