Gapmers: Invention and Early History.

Gapmers are antisense oligonucleotides composed of a central DNA segment flanked by nucleotides of modified chemistry. Hybridizing with transcripts by sequence complementarity, gapmers recruit ribonuclease H and induce target RNA degradation. Since its concept first emerged in the 1980s, much work has gone into developing gapmers for use in basic research and therapy. These include improvements in gapmer chemistry, delivery, and therapeutic safety. Gapmers have also successfully entered clinical trials for various genetic disorders, with two approved by the US Food and Drug Administration for the treatment of familial hypercholesterolemia and transthyretin amyloidosis-associated polyneuropathy, and one approved by the European Commission for the treatment of familial chylomicronemia syndrome. Here, we review the events surrounding the early development of gapmers, from conception to their maturity, and briefly conclude with perspectives on their use in therapy.