Disease-Modifying Therapies for Hereditary Transthyretin Amyloidosis with Polyneuropathy: Current Status and Future Perspectives.

Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is an autosomal dominant disorder caused by pathogenic variants in the transthyretin (TTR) gene resulting in progressive sensorimotor neuropathy, autonomic dysfunction, and effects on other organs, particularly the heart. Historically, treatment options have been limited to liver transplantation and symptomatic management, and the disease was associated with poor prognosis and progressive disability. However, over the past decade, the therapeutic landscape has been transformed by the development of disease-modifying therapies that target the underlying pathophysiology of TTR amyloid formation. These therapies include TTR stabilizers, such as tafamidis, diflunisal, and acoramidis, as well as RNA-silencing agents, such as patisiran, vutrisiran, inotersen, and eplontersen, which reduce hepatic production of TTR and slow disease progression. Clinical trials of RNA interference therapies have demonstrated significant improvements in neuropathy impairment scores, quality of life, and functional outcomes, with acceptable safety profiles and sustained long-term benefits. Emerging gene-editing approaches, including CRISPR-based therapies like NTLA-2001, may provide a one-time treatment and long-term disease control, representing a promising future direction for managing ATTRv-PN. Despite these advances, important challenges remain. These include high treatment costs, limited global accessibility, uncertainty regarding optimal treatment selection and sequencing, and the need for long-term real-world, patient-centered outcome data. This review summarizes current disease-modifying therapies for ATTRv-PN, compares their mechanisms and clinical evidence, and discusses unmet needs and future research directions, with the aim of providing a practical and comprehensive overview for clinicians treating patients with ATTRv-PN.