Nucleic acid therapeutics (oligonucleotides)

Nucleic acid therapeutics are short synthetic oligonucleotides — small interfering RNA (siRNA) and antisense oligonucleotides (ASO) — designed to bind a specific messenger RNA and either silence it (RNAi/ RNase H) or reprogram its splicing. Unlike messenger-RNA drugs (covered in the sibling mRNA platforms article) or viral gene therapy, oligonucleotides are chemically synthesised, tunable and increasingly delivered by simple subcutaneous injection thanks to GalNAc liver targeting. Alnylam leads RNAi commercially with AMVUTTRA (vutrisiran) for ATTR amyloidosis, marking one year of the U.S. launch in the first quarter of 2026; Ionis, the antisense pioneer, has a zilganersen New Drug Application for Alexander disease accepted for FDA Priority Review and licensed to Recordati outside the US; Sarepta’s Duchenne ASOs Amondys 45 and Vyondys 53 are under FDA supplemental review with decisions expected by February 2027; and Silence Therapeutics (UK) is advancing an siRNA pipeline in rare blood and cardiometabolic disease.

The key directions of nucleic acid therapeutics are:

1. RNA interference (siRNA) therapeutics (siRNA/RNAi): GalNAc-conjugated siRNA silencing hepatic disease targets by Watson-Crick pairing and RISC-mediated mRNA cleavage — Alnylam (AMVUTTRA, Onpattro), Silence Therapeutics.
2. Antisense oligonucleotides (ASO): RNase-H-degrading or splice-switching ASOs that redirect mRNA processing — Ionis (Spinraza, zilganersen), Sarepta (Amondys 45, Vyondys 53).
3. Oligonucleotide delivery and chemistry (GalNAc Conjugation): N-acetylgalactosamine ligands for hepatocyte targeting, plus 2’-MOE / 2’-OMe / constrained-ethyl sugar and phosphorothioate backbone modifications for stability and potency.
4. Rare, neurological and cardiometabolic indications (Rare Disease): ATTR amyloidosis, spinal muscular atrophy, Duchenne muscular dystrophy, Alexander disease and rare blood disorders — the therapeutic beachheads where oligonucleotides first commercialised.

Sectoral value chain#

[disease gene / mRNA target] ──> [ASO / siRNA design + GalNAc] ──> [synthetic oligonucleotide drug]
                                              │
                                     (subcutaneous / systemic)
                                              │
                                              ▼
[approved drug] <─── [clinical trial + GMP manufacture] <─────┘

Value chain levels#

Cross-cutting technologies of the sector:

• GalNAc liver targeting (GalNAc Conjugation): Alnylam, Ionis and Silence all use N-acetylgalactosamine conjugation to route subcutaneous oligonucleotides to hepatocytes, turning oligonucleotides into out-patient drugs.
• Sugar and backbone chemistry (Oligonucleotide Chemistry): 2’-O-methoxyethyl (Ionis), constrained-ethyl and 2’-OMe/2’-F (Alnylam) sugars plus phosphorothioate backbones deliver nuclease stability, binding affinity and potency.
• Mechanism diversity (Mechanism): RNase-H-degrading ASOs (Ionis, Sarepta), splice-switching ASOs (Sarepta Duchenne) and RISC-cleaving siRNA (Alnylam, Silence) cover a wide mechanistic surface from one chemical class.

The stack pairs precision sequence design with medicinal chemistry (sugars, backbone, conjugate) and a delivery strategy, so a synthetic oligonucleotide reaches its tissue and engages its mRNA in an out-patient setting.

1. RNA interference (siRNA/RNAi):
   • Alnylam’s GalNAc-conjugated siRNA AMVUTTRA (vutrisiran) silences the TTR mRNA in hepatocytes and is approved for both forms of ATTR amyloidosis, with Q1 2026 marking one year of the U.S. ATTR-CM launch.
   • Silence Therapeutics applies its mRNAi GOLD platform to siRNA candidates in rare blood and cardiometabolic disease, reporting promising 2026 clinical results.
2. Antisense oligonucleotides (ASO):
   • Ionis’s zilganersen (Alexander disease) NDA is under FDA Priority Review and licensed to Recordati ex-US, extending the Spinraza (SMA) antisense franchise.
   • Sarepta’s Amondys 45 and Vyondys 53 splice-switching ASOs are under supplemental FDA review for full approval in Duchenne, with decisions expected by February 2027.
3. Delivery and chemistry (GalNAc Conjugation):
   • GalNAc conjugation routes subcutaneous oligonucleotides to hepatocytes, while 2’-MOE (Ionis), constrained-ethyl and 2’-OMe/2’-F (Alnylam) sugars with phosphorothioate backbones deliver the stability and affinity needed for in-vivo potency.
   • This chemistry-and-delivery layer is what converted oligonucleotides from research tools into repeat-dose subcutaneous drugs.