AI Article Synopsis

  • Transthyretin (TTR) is a protein produced mostly by the liver, but it can misfold and form harmful amyloid fibrils, leading to a condition called ATTR amyloidosis, particularly affecting the heart and nerves.
  • Treatment strategies for ATTR amyloidosis involve blocking TTR production, stabilizing its structure, or disrupting the amyloid fibrils, with promising therapies like siRNA (patisiran) and antisense oligonucleotides (inotersen) already approved for certain patients.
  • Current clinical trials are exploring further treatments with other siRNA and ASO formulations, as well as innovative genome editing technologies like CRISPR-Cas9, to enhance the management of ATTR amyloidosis

Article 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.

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Source
http://dx.doi.org/10.1038/s41569-022-00683-zDOI Listing

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