On December 22, 2023, the U.S. Food and Drug Administration approved Eplontersen. And it is indicated for the study of transthyretin amyloid cardiomyopathy (ATTR-CM). Morever ATTR-CM is a systemic, progressive, and fatal disease that leads to progressive heart failure and death within 3 to 5 years after onset.

Transthyretin (TTR), formerly known as thyroxine-binding prealbumin, is a tetrameric protein transporting hormones in the plasma and brain. It forms a complex with retinol-binding protein (RBP). And this complex facilitates the transport of thyroid hormones and vitamin A in the blood and cerebrospinal fluid. TTR is a positive indicator of nutrition status. And it also is negatively correlated with inflammation. TTR is a neuroprotective and oxidative-stress-suppressing factor. Mutations, oxidative modifications, aging, proteolysis, and metal cations, including Ca2+ destabilize structure of TTR. Destabilized TTR molecules form amyloid deposits, resulting in senile and familial amyloidopathies.

Eplontersen is a Ligand-conjugated Antisense Oligonucleotide for Polyneuropathy of Hereditary Transthyretin Amyloidosis research

Eplontersen is a triantennary N-acetyl galactosamine (GalNAc₃-7a)-conjugated antisense oligonucleotide targeting transthyretin (TTR) mRNA to inhibit production of both variant and wild-type TTR protein. What’s more, misfolded TTR induces amyloid fibrils formation in the heart and peripheral nerves, leads to amyloid TTR (ATTR) amyloidosis diseases. Therefore, Eplontersen can be used in transthyretin amyloid cardiomyopathy (ATTR-CM) research.

In Vitro, Eplontersen mediates N-acetylgalactosamine moiety targeting the oligonucleotide to cells bearing an asialoglycoprotein receptor. And in Vivo, Eplontersen (682884) (0.6, 2, 6 mg/kg; s.c.; once a week for 3 weeks) inhibits TTR protein expression in a dose-dependent manner in vivo, without affecting normal growth in transgenic C57BL/6 mice expressing human transthyretin (TTR).

In conclusion, Eplontersen is a Ligand-conjugated antisense oligonucleotide for polyneuropathy of hereditary transthyretin amyloidosis research.

Reference:

[1]. Nat Rev Cardiol. 2022 Mar 23. 

[2]. Br J Clin Pharmacol. 2022 Jul 22. 

[3]. WO2014179627[P]. 2014-11-06.