Development and Clinical Applications of Antisense Oligonucleotide Gapmers.

Antisense oligonucleotides (AONs) are synthetic oligonucleotides designed to bind target RNA and have opened new treatment possibilities for genetic diseases by regulating gene expression. AONs are often used to suppress the expression of mutated genes, which may interfere with essential downstream pathways. Since AONs have been introduced for clinical use, different chemistries have been developed to further improve efficacy, potency, and safety. One such chemistry is a chimeric structure of a central block of deoxyribonucleotides flanked by sequences of modified nucleotides. Referred to as a gapmer, this chemistry produced promising results in the treatment of genetic diseases. Tofersen is an example of a recently FDA-approved antisense oligonucleotide gapmer used for the treatment of amyotrophic lateral sclerosis. Many others are being tested in clinical trials or under preclinical development. This chapter will cover advancements in gapmer treatments for various diseases, including familial hypercholesterolemia, hereditary transthyretin amyloidosis, cancer, familial chylomicronemia syndrome, familial partial lipodystrophy, familial hypertriglyceridemia, Huntington's disease, myotonic dystrophy, prion diseases, and amyotrophic lateral sclerosis.