Eplontersen

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. Misfolded TTR induces amyloid fibrils formation in the heart and peripheral nerves, leads to amyloid TTR (ATTR) amyloidosis diseases[1][2][3].

Signaling Pathways >> Others >> Others

Research Areas >> Neurological Disease

TTR[1], asialoglycoprotein receptor[3]

Eplontersen mediates N-acetylgalactosamine moiety targeting the oligonucleotide to cells bearing an asialoglycoprotein receptor[3].

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)[3]. Animal Model: Transgenic C57BL/6 mice expressing human transthyretin (TTR) (8-week-old)[3] Dosage: 0.6, 2, 6 mg/kg Administration: Subcutaneous injection; once a week for 3 weeks; performed tail bleeds at various time point; sacrificed mice 72 h following the final administration Result: Decreased TTR mRNA level to 15%, and reduced plasma TTR protein levels to 21% at 6 mg/kg on day 17 after injection. Showed no significant effect on plasma ALT and AST level, no inhibition on body weight, organ weight, spleen weight, and kidney weight as well.

[1]. Aimo A, et al. RNA-targeting and gene editing therapies for transthyretin amyloidosis. Nat Rev Cardiol. 2022 Mar 23.

[2]. Diep JK, et al. Population pharmacokinetic/pharmacodynamic modelling of eplontersen, an antisense oligonucleotide in development for transthyretin amyloidosis. Br J Clin Pharmacol. 2022 Jul 22. 

[3]. Prakash Thazha P, et al. Antisense oligonucleotides to hepatitis B virus RNA or transthyretin mRNA conjugated with N-acetylgalactosamine targeting moieties: World Intellectual Property Organization, WO2014179627[P]. 2014-11-06.