Mipomersen is a 20-mer phosphorothioate oligonuleotide with underlined residues containing 2'-O-(2-methoxyethyl) nucleosides; all other residues are 2'-deoxynucleosides. Substitution at the 5-position of cytosine (C) and uracil (U) bases with a methyl group is indicated by MeC or MeU. Mipomersen (also known as ISIS 301012) was approved with orphan drug status by the US FDA in January 2013 as an adjunct to lipid-lowering medications and diet to reduce low density lipoprotein-cholesterol (LDLC), apolipoprotein B (Apo B), total cholesterol (TC), and non-high density lipoprotein-cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH). Mipomersen is an anti-sense oligonucleotide (ASO) designed to inhibit Apo B100 transcription by Watson Crick pairing to the mRNA sequence to target the complex for silencing and elimination, often via RNase H1 degradation.Mipomersen is synthesized via solid-phase nucleotide synthesis involving sequential addition of nucleotide phosphoramidates, with subsequent phosphorothiolation via phenylacetyldisulfide.
