Nucleic acid therapeutics (oligonucleotides)

01Overview and value chain

Markers: [EC: ATMP Regulation (EC No 1394/2007) + FDA oligonucleotide drug guidance | OECD: Bio-pharma | Regulator: FDA (USA), EMA (European Union), NMPA (China)]

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.

02US

The US anchors oligonucleotide therapeutics commercially — Alnylam, Ionis and Sarepta are all US-based, NASDAQ-listed, and hold the approved-drug franchise.

Alnylam, Ionis, Sarepta, FDA review

• Alnylam: the leading RNAi company; AMVUTTRA (vutrisiran) is approved for both forms of ATTR amyloidosis, with the first quarter of 2026 marking one year since the U.S. ATTR-CM launch — a significant commercial milestone; earlier siRNA product patisiran failed a 2023 FDA review before vutrisiran succeeded by redesigning the trial.
• Ionis Pharmaceuticals: the antisense pioneer; the FDA has accepted for Priority Review the New Drug Application for zilganersen in Alexander disease, and Ionis has licensed zilganersen to Recordati for all countries outside the US, extending its Spinraza (nusinersen, SMA) heritage.
• Sarepta Therapeutics: its Duchenne muscular dystrophy ASOs Amondys 45 (casimersen) and Vyondys 53 (golodirsen) are under supplemental FDA review for full approval, with decisions expected by February 28, 2027, alongside ongoing ESSENCE readouts.
• FDA framework: oligonucleotide drugs are reviewed as New Drug Applications under FDA guidance, with post-market requirements; the FDA’s 2023 patisiran versus 2025 vutrisiran decisions show trial design — not mechanism — driving outcomes.

03CN

China’s oligonucleotide therapeutics field is emerging, concentrated in platform start-ups and mRNA-adjacent work rather than a deep approved siRNA/ASO franchise.

emerging oligo platforms, NMPA pathway

• Emerging platforms: domestic biotechs (e.g. Ribo Life Science and peers) are building siRNA/mRNA platforms, but enrichment returned platform and pipeline coverage rather than a source-confirmed approved Chinese oligonucleotide drug, so the CN block is treated qualitatively.
• NMPA pathway: oligonucleotide drugs are reviewed under the National Medical Products Administration’s drug framework, with GalNAc-siRNA candidates entering clinical development behind the US/EU leaders.
• CRO/CDMO pull: China’s oligonucleotide manufacturing base (WuXi etc.) supports global supply, linking the domestic emerging field to the worldwide CMO/CDMO tier.

04EU

Europe contributes the RNAi pipeline of Silence Therapeutics (UK) and the EU regulator EMA, which authorises oligonucleotide drugs centrally.

Silence Therapeutics, EMA, ATMP context

• Silence Therapeutics (United Kingdom): advancing an siRNA pipeline in rare blood and cardiometabolic disease on its mRNAi GOLD platform, with promising 2026 clinical results reported in its June 2026 corporate presentation.
• EMA framework: oligonucleotide drugs receive central EU marketing authorisation from the European Medicines Agency; advanced-therapy classification (ATMP) applies where the product borders gene therapy, under Regulation (EC) No 1394/2007.
• EU manufacturing and licensing: EU firms license US-origin oligonucleotide assets (e.g. Recordati’s ex-US zilganersen license from Ionis), and European CDMOs participate in the GMP synthesis supply chain.

05Leading companies and research institutes

06Tech stack and innovations

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.

07Value chains and production pipelines

Industrial pipeline of an oligonucleotide drug (FDA NDA / EMA MAA, ATMP Regulation)

┌───────────────────────────┐      ┌───────────────────────────┐
│ 1. Target & sequence      │ ───> │ 2. Synthesis &            │
│    design                 │      │    modification           │
└───────────────────────────┘      └───────────────────────────┘
                                                   │
                                                   ▼
┌───────────────────────────┐      ┌───────────────────────────┐
│ 4. Preclinical & clinical │ <─── │ 3. Formulation & delivery │
└───────────────────────────┘      └───────────────────────────┘
              │
              ▼
┌───────────────────────────┐      ┌───────────────────────────┐
│ 5. Regulatory &           │ ───> │ 6. Launch &               │
│    GMP manufacture        │      │    pharmacovigilance      │
└───────────────────────────┘      └───────────────────────────┘

Stage 1: Target and sequence design

The disease mRNA is identified from genomics and a lead ASO or siRNA sequence is designed against it by Watson-Crick base-pairing rules, screened in cell-based assays.

Stage 2: Synthesis and modification

The lead sequence is synthesised by solid-phase oligonucleotide synthesis with sugar (2’-MOE, cEt, 2’-OMe/2’-F) and phosphorothioate backbone modifications, and conjugated to a GalNAc or other targeting ligand to form the drug substance.

Stage 3: Formulation and delivery

The modified oligonucleotide is formulated for its delivery route — typically subcutaneous for GalNAc-siRNA, occasionally LNP for extra-hepatic targets — to produce the drug product.

Stage 4: Preclinical and clinical

IND-enabling pharmacology, pharmacokinetics and toxicology support first-in-human trials, then pivotal trials (such as ATTR for vutrisiran, Duchenne for Amondys 45, Alexander disease for zilganersen) generate the efficacy and safety dataset.

Stage 5: Regulatory and GMP manufacture

A CMO/CDMO scales GMP oligonucleotide synthesis, and the sponsor files an NDA (US) or MAA (EU); the FDA accepted zilganersen for Priority Review and Sarepta’s sNDAs are under review with February 2027 decisions.

Stage 6: Launch and pharmacovigilance

Following approval, the drug launches to market access and patient-access programmes with post-market pharmacovigilance — as Alnylam is executing for AMVUTTRA one year after the U.S. ATTR-CM launch.