Transthyretin (TTR) is a tetrameric
protein synthesized mostly by the liver and secreted into the plasma. TTR molecules can misfold and form
amyloid fibrils in the heart and peripheral nerves, either as a result of gene variants in TTR or as an ageing-related phenomenon, which can lead to
amyloid TTR (ATTR)
amyloidosis. Some of the proposed strategies to treat ATTR
amyloidosis include blocking TTR synthesis in the liver, stabilizing TTR tetramers or disrupting TTR fibrils.
Small interfering RNA (
siRNA) or
antisense oligonucleotide (ASO) technologies have been shown to be highly effective for the blockade of TTR expression in the liver in humans. The
siRNA patisiran and the ASO
inotersen have been approved for the treatment of patients with ATTR variant
polyneuropathy, regardless of the presence and severity of ATTR
cardiomyopathy. Preliminary data show that
therapy with
patisiran improves the cardiac phenotype rather than only inducing disease stabilization in patients with ATTR variant
polyneuropathy and concomitant ATTR
cardiomyopathy, and this
drug is being evaluated in a phase III clinical trial in patients with ATTR
cardiomyopathy. Furthermore, ongoing phase III clinical trials will evaluate another
siRNA, vutrisiran, and a novel ASO formulation, eplontersen, in patients with ATTR variant
polyneuropathy or ATTR
cardiomyopathy. In this Review, we discuss these approaches for TTR silencing in the treatment of ATTR
amyloidosis as well as the latest strategy of genome editing with CRISPR-Cas9 to reduce TTR gene expression.