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RNA-targeting and gene editing therapies for transthyretin amyloidosis

Abstract

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.

Key points

  • Transthyretin (TTR) is a tetrametric protein synthesized mainly by the liver that can misfold and deposit as amyloid fibrils, predominantly in peripheral nerves and the heart, which can result in amyloid TTR (ATTR) amyloidosis.

  • Therapeutic options for ATTR amyloidosis include pharmacological agents that inhibit hepatic synthesis of TTR, stabilize the tetramer or disrupt the amyloid fibrils.

  • The small interfering RNA (siRNA) patisiran and the antisense oligonucleotide (ASO) inotersen block liver TTR expression and have been approved for the treatment of variant ATTR polyneuropathy (ATTRv-PN).

  • Phase III trials are ongoing on patisiran for the treatment of ATTR cardiomyopathy (ATTR-CM) and the siRNA vutrisiran for hereditary ATTRv-PN or ATTR-CM.

  • A novel ASO formulation, eplontersen, is being evaluated in phase III trials in patients with ATTRv-PN or ATTR-CM.

  • A genome editing strategy using CRISPR–Cas9 to silence the TTR gene is being investigated in a phase I trial.

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Fig. 1: RNA-targeting and gene editing strategies for the treatment of amyloid TTR amyloidosis.

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A.A. researched data for the article. A.A., C.R. and M.E. contributed substantially to discussion of the content. A.A., V.C. and G.P. wrote the article. A.A., C.R., M. Franzini, G.V., J.G., M. Fontana, C.P. and M.E. reviewed and/or edited the manuscript before submission.

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Correspondence to Alberto Aimo.

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Aimo, A., Castiglione, V., Rapezzi, C. et al. RNA-targeting and gene editing therapies for transthyretin amyloidosis. Nat Rev Cardiol 19, 655–667 (2022). https://doi.org/10.1038/s41569-022-00683-z

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