Oligonucleotide drug discovery: its journey through time.

1970s-1980s: The birth of the antisense approach

The antisense concept was first demonstrated in 1978, when Paul Zamecnik and Mary Stephenson used a 13-nucleotide DNA oligonucleotide to inhibit Rous sarcoma virus replication and protein translation in chicken fibroblasts.^1,2 This was the first experimental proof that a short synthetic sequence could selectively block gene expression.

In the years that followed, researchers uncovered the mechanistic basis of antisense activity, most notably the role of RNase H, an enzyme that degrades RNA in RNA–DNA hybrids.³ These discoveries established the foundation for antisense drug design, but it wasn’t until the late ‘90s that therapeutic breakthroughs occurred.

1990s-2000s: First approvals and trials

After years of refinement, the first clinical breakthrough arrived in 1998 with the FDA approval of fomivirsen, a synthetic antisense oligonucleotide (ASO) developed by Isis Pharmaceuticals (now Ionis Pharmaceuticals) for the treatment of cytomegalovirus (CMV) retinitis.⁴ This was the first ASO approved for human use.

Around the same time, a different form of gene silencing was discovered. In 1998, Andrew Fire and Craig Mello published their landmark discovery of RNA interference (RNAi) in C. elegans, revealing a natural mechanism for gene silencing.⁵ Their work, recognized with the 2006 Nobel Prize in Physiology and Medicine,⁶ opened an entirely new approach to oligonucleotide therapeutics.

By 2004, the first siRNA-based clinical trial had begun. The candidate, Sirna-027 (AGN211745) developed by Sirna Therapeutics and Allergan, targeted VEGFR-1 mRNA for the treatment of neovascular age-related macular degeneration (AMD).⁷ Although early results confirmed safety and target engagement, the program was discontinued after a phase II trial failed to demonstrate sufficient efficacy.⁸

Despite setbacks, these pioneering efforts validated oligonucleotides as a therapeutic class and initiated innovations in chemical modification and delivery systems that underpin today’s successes.

2010s: Breakthroughs in rare diseases

The 2010s marked a turning point for the oligonucleotide therapeutics field, with several breakthrough approvals for rare diseases:

• 2013: Mipomersen (Kynamro®), an ASO targeting ApoB-100 mRNA, was approved by the FDA for the treatment of homozygous familial hypercholesterolemia.
• 2016: Eteplirsen (Exondys 51®) received accelerated FDA approval for Duchenne muscular dystrophy (DMD), specifically inducing exon 51 skipping in the dystrophin gene.
• 2016: Defibrotide (Defitelio®), a natural deoxyribonucleotide mixture, was approved by the FDA for the treatment of hepatic veno-occlusive disease with renal or pulmonary dysfunction following hematopoietic stem cell transplantation.
• 2016: Nusinersen (Spinraza®) became the first intrathecally administered ASO approved to treat spinal muscular atrophy (SMA).

This decade also saw the emergence of N-acetylgalactosamine (GalNAc)-conjugated siRNA technology, which enabled precise, receptor-mediated delivery of oligonucleotides to the liver. The GalNAc ligand binds specifically to the asialoglycoprotein receptor (ASGPR), which is highly expressed on hepatocytes, allowing the siRNA to be efficiently internalized and reach its target mRNA.

2020s: The era of precision oligo medicines

Over the last five years, oligonucleotide-based therapeutics have continued to achieve major regulatory milestones, expanding their reach beyond rare genetic diseases into broader indications:

• 2021: Inclisiran (Leqvio®), a GalNac-conjugated siRNA, was approved by the FDA for the reduction of LDL cholesterol in adults with atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia.
• 2023: Tofersen (Qalsody™), an ASO, received accelerated FDA approval for the treatment of ALS in patients with SOD1 mutations.
• 2024: Imetelstat (Omblastys®), a telomerase-inhibiting oligonucleotide, was approved by the FDA for the treatment of transfusion-dependent myelodysplastic syndromes.

Together, these approvals mark the rapid evolution of oligonucleotides into precision medicines.

Future outlook

By the end of 2024, a total of 20 oligonucleotide drug products had received commercial approval in the US and EU for a range of diseases,⁹ with many more in late-stage clinical development.

2025 has seen a focus on expanding delivery systems to reach tissues beyond the liver and central nervous system, applying AI and machine learning to accelerate discovery, design, and optimization of new oligonucleotide sequences and targets, and developing more stable and effective chemical modifications.

Looking ahead to 2026 and beyond, research is likely to extend beyond rare diseases toward chronic conditions, neurodegenerative diseases, and cancers, leveraging the precise modulation of gene expression and cellular function to achieve lasting therapeutic benefit.