Transthyretin (TTR or TBPA) is a transporter of thyroid hormone and retinol-binding protein found in plasma and cerebrospinal fluid. It can act as the primary carrier of the thyroid hormone thyroxine (T4) as well as a carrier of retinol (vitamin A) by binding to retinol-binding protein (RBP) in blood and cerebrospinal fluid. TTR is a termer of four identical subunits of a 127 amino acid peptide/protein, encoded by the TTR gene located on chromosome 18. Besides, it can produce in the liver, choroid plexus, and retinal pigment epithelium. And it exists in the bloodstream, cerebrospinal fluid and eye, respectively.

To date, more than 100 TTR gene variants have been reported, at least 95 of which are associated with TTR amyloidosis (ATTR). ATTR is the most common autosomal dominant genetic disorder. It is characterized by an abnormal accumulation of amyloid deposits consisting of misfolded transthyretin proteins in body organs and tissues, including wild-type transthyretin amyloidosis, hereditary transthyretin amyloidosis, familial amyloid polyneuropathy (FAP), and familial amyloid cardiomyopathy (FAC). Therefore, TTR can be used as a therapeutic target for these diseases.

Eplontersen is an oligonucleotide targeting TTR mRNA.

From: Kristen AV, et al. Neurodegener Dis Manag. 2019 Feb;9(1):5-23.

Eplontersen is a trisynaptic, N-acetylgalactosamine (GalNAc3)-spliced antisense oligonucleotide. It targets the mRNA of the thyrotropin transport protein TTR and inhibits both variant and wild-type TTR production. Eplontersen can mediate N-acetylgalactosamine moiety by targeting the oligonucleotide to cells bearing an asialoglycoprotein receptor. Moreover, Eplontersen (0.6-6 mg/kg; once a week) inhibits TTR protein expression in a dose-dependent manner by subcutaneous injection for three weeks in transgenic C57BL/6 mice (8 weeks old) expressing human TTR. In addition, on day 17 post-injection, it reduces TTR mRNA levels to 15% and plasma TTR protein levels to 21% at a dose of 6 mg/kg. Importantly, Eplontersen treatment has no significant effect on plasma alanine transferase (ALT) and aspartate transferase (AST) levels. Also, it does not inhibit body weight, organ weight, spleen weight, or kidney weight, i.e. That is, Eplontersen does not affect the normal growth of the mice.

In conclusion, Eplontersen is an antisense oligonucleotide capable of targeting the mRNA of the thyroxine transport protein TTR and inhibiting both variant and wild-type TTR production.

Reference：

[1] Alberto Aimo, et al. Nat Rev Cardiol. 2022 Oct;19(10):655-667.
[2] Prakash Thazha P, et al. WO2014179627[P]. 2014-11-06.