Hereditary transthyretin amyloid neuropathies: advances in pathophysiology, biomarkers, and treatment.

Hereditary transthyretin (TTR) amyloid polyneuropathy is an autosomal dominant life-threatening disorder. TTR is produced mainly by the liver but also by the choroid plexus and retinal pigment epithelium. Detailed clinical characterisation, identification of clinical red flags for misdiagnosis, and use of biomarkers enable early diagnosis and treatment. In addition to liver transplantation and TTR stabilisers, three other disease-modifying therapies have regulatory approval: one antisense oligonucleotide (inotersen) and two small interfering RNAs (siRNAs; patisiran and vutrisiran). The siRNAs have been shown to stop progression of neuropathy and improve patients' quality of life. As none of the disease-modifying therapies can cross the blood-brain barrier, TTR deposition in the CNS, which can cause stroke and cognitive impairment, remains an important unaddressed issue. CRISPR-Cas9-based one-time TTR editing therapy is being investigated in a phase 1 clinical study. Identification of the earliest stages of pathogenesis in TTR variant carriers is a major challenge that needs addressing for optimal management.

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Declaration of interests DA was a consultant for Alnylam, Bridgebio, Pfizer, and AstraZeneca; and received support for travel from Alnylam. MMR was a consultant for Alnylam, Akcea; received a research grant from Alnylam and honoraria for chairing a symposium for the company; and declared consultancy compensation for being on a steering committee of Eidos Therapeutics. YS received compensation for consulting activities from Alnylam and Pfizer; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, and educational events from Alnylam and Pfizer; and declares receiving research grants Alnylam and Pfizer. MP received compensation for consulting work from Pfizer, Alnylam, Vertex, Intellia, AstraZeneca, and Ionis. IC was a consultant for Alnylam and Pfizer; received honoraria for lectures, presentations, speakers bureaus, manuscript writing, and educational events from Pfizer, Sobi, and Alnylam; received financial support for meetings and travel from Pfizer and Alnylam; and declares receiving research funding from Pfizer. MW-C was a consultant for Ionis, Para Tu Consulta, Alnylam, Pfizer, Prothena, and AstraZeneca; and received support for attending meetings and for travel Pfizer, Ionis, and PTC. AE-L was a consultant for Alnylam; was supported by Alnylam and Pfizer to travel to attend meetings; declares receiving honoraria for lectures, presentations, speakers bureaus, manuscript writing, and educational events from Alnylam and Pfizer; and received payment for participation in a data safety monitoring board for Intellia.