Emerging therapies in transthyretin amyloidosis – a new wave of hope after years of stagnancy?

Abstract

Transthyretin amyloidosis (ATTR) is a rare, yet underdiagnosed disease characterized by progressive impairment of neurologic and cardiac function due to deposition of misfolded transthyretin. Despite great efforts, such as the introduction of orthotopic liver transplant, the devastating prognosis for both variant and wild‐type ATTR patients remained unchanged over the last decades, mainly due to a lack of specific therapies. Fortunately, recent years saw the introduction of promising targeted therapies, which aim to interfere with the deposition of misfolded transthyretin (TTR) at various stages of the cascade underlying ATTR progression. These include TTR tetramer stabilizers (tafamidis, diflunisal, epigallocatechin‐3‐gallate), TTR silencers (inotersen, patisiran) and fibril disruptors (monoclonal antibodies, doxycycline and tauroursodeoxycholic acid). In the context of this review we explain their mechanisms of action, analyse their efficacy on neurologic and cardiac function based on all clinical trials conducted to date and discuss their clinical applicability. Eventually suggestions for future clinical research into the field are provided.

Hereditary transthyretin amyloidosis overview

“…Elucidation in molecular pathogenic mechanisms and progress in pharmacological technologies led to an unexpected therapeutic revolution in ATTRv amyloidosis. A wide spectrum of targeted therapies already obtained market access and some others are close to achieve it [58,59].…”

Refining the role of carpal tunnel syndrome in cardiac amyloidosis

“…Detection of amyloidosis before a diagnostic cardiac phenotype develops is indeed compelling, as novel therapeutic agents are emerging 7 and as they appear to be more effective if initiated before severe heart failure develops. 8 This notion was also highlighted in a report by Canepa et al, 9 examining characteristics of 507 real-world CA patients and finding them clinically comparable to those enrolled in the ATTR-ACT trial, suggesting a possibility of offering treatment to a larger number of subjects expected to benefit from it.…”

January 2020 at a glance: translational medicine, predictors of outcome and treatments

“…Target therapy for transthyretin amyloidosis is one of the main recent achievements in HF treatment. 3 Müller et al 4 reviewed evidence about new specific drugs targeting transthyretin amyloidosis and potential future implications. Berulava et al 5 found that about one quarter of the transcripts of healthy mouse and human heart exhibit m6-adenosine methylation (m6A) of RNA.…”

“…Target therapy for transthyretin amyloidosis is one of the main recent achievements in HF treatment . Müller et al . reviewed evidence about new specific drugs targeting transthyretin amyloidosis and potential future implications.…”