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RNA-targeting and gene editing therapies for transthyretin amyloidosis

Aimo, Alberto; Castiglione, Vincenzo; Rapezzi, Claudio; Franzini, Maria; Panichella, Giorgia; Vergaro, Giuseppe; Gillmore, Julian; ... Emdin, Michele; + view all (2022) RNA-targeting and gene editing therapies for transthyretin amyloidosis. Nature Reviews Cardiology , 19 (10) 10.1038/s41569-022-00683-z. Green open access

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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.

Type: Article
Title: RNA-targeting and gene editing therapies for transthyretin amyloidosis
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41569-022-00683-z
Publisher version: https://doi.org/10.1038/s41569-022-00683-z
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Cardiac & Cardiovascular Systems, Cardiovascular System & Cardiology, SHORT INTERFERING RNA, LIVER-TRANSPLANTATION, LATE-ONSET, POLYNEUROPATHY, TAFAMIDIS, EFFICACY, SAFETY, CARDIOMYOPATHY, PREVALENCE, PATISIRAN
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: https://discovery.ucl.ac.uk/id/eprint/10161200
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