From a Concept on a Chalkboard to Gapmer Antisense

Gapmer antisense oligonucleotides emerged from our efforts to improve the stability, affinity, and potency of early phosphodiester and phosphorothioate (PS) antisense oligonucleotides. Working with Paul Zamecnik during the late 1980s and early 1990s, I witnessed the transition from a simple steric-block model of antisense action to the recognition of RNase H as the central driver of potency. Our systematic exploration of backbone and sugar modifications revealed the limitations of single-chemistry approaches and led to the development of hybrid antisense constructs that combined deoxyribonucleotide with 2'-modified ribonucleotide segments, all PS-modified. Such designs later became known as gapmers and provided enhanced stability, improved affinity, and efficient RNase H activation. Although our initial efforts with phosphorothioate oligonucleotides faltered in the clinic, continued refinement of the hybrid designs ultimately enabled the development of multiple approved drugs. Here I describe how a concept sketched on a chalkboard evolved into a widely adopted therapeutic platform.