Modified oligonucleotides for therapeutic discovery

Antisense oligonucleotides, splice-switching oligonucleotides, siRNA, miRNA, CRISPR guide RNAs and aptamers have specific design requirements. All require sufficient in vivo stability and efficient target engagement. Conjugation of lipids or targeting moieties can enhance cellular uptake, tissue-specific delivery, pharmacokinetic properties and, in some cases, overall oligonucleotide stability.

Why therapeutic oligonucleotides matter

Oligonucleotide therapeutics have evolved from a niche technology into a validated and rapidly expanding drug class. Since 1998, around 20 oligonucleotide-based medicines have received regulatory approval, spanning antisense, exon-skipping, siRNA and miRNA mechanisms across diverse diseases, with approvals accelerating in the past five years. By enabling selective modulation of previously difficult-to-drug biological targets, oligonucleotides are opening therapeutic opportunities in diseases previously considered untreatable with conventional approaches. Yet the field is still in its early stages, with substantial potential for new chemistries, conjugates and delivery strategies to expand the reach of this modality.

See a timeline of selected oligonucleotide approvals

Year	Drug	Mechanism	Indication	Company
1998	Fomivirsen	ASO	Ocular cytomegalovirus	Novartis
2013	Mipomersen	ASO	Familial hypercholesterolaemia	Genzyme / Isis
2016	Eteplirsen	Exon skipping	Duchenne muscular dystrophy	Sarepta
2016	Nusinersen	Splice switching	Spinal muscular atrophy	Biogen
2018	Inotersen	ASO	Hereditary transthyretin amyloidosis	Akcea
2018	Patisiran	siRNA	Hereditary transthyretin amyloidosis	Alnylam
2019	Givosiran	siRNA	Acute hepatic porphyria	Alnylam
2019	Golodirsen	Exon skipping	Duchenne muscular dystrophy	Sarepta
2019	Volanesorsen	ASO	Familial chylomicronaemia syndrome	Akcea
2020	Inclisiran	siRNA	Hypercholesterolaemia	Novartis
2020	Lumasiran	siRNA	Primary hyperoxaluria type 1	Alnylam
2021	Casimersen	Exon skipping	Duchenne muscular dystrophy	Sarepta
2023	Tofersen	ASO	SOD1 amyotrophic lateral sclerosis	Biogen
2023	Eplontersen	ASO	Hereditary transthyretin amyloidosis	Ionis / AstraZeneca
2025	Fitusiran	siRNA	Haemophilia A and B	Sanofi / Alnylam
2025	Donidalorsen	ASO	Hereditary angioedema	Ionis
2025	Plozasiran	siRNA	Familial chylomicronaemia syndrome	Arrowhead

Where we can help

We provide the design and synthesis of chemically optimised oligonucleotides, including modified sequences and conjugates, to support the evaluation of promising candidates for therapeutic development and enable efficient progression from concept to experimental testing.

Early discovery: lead optimisation and oligonucleotide design support, so candidate sequences are chemically sound before they move into testing
Scale-up: synthesis from small discovery-scale batches through to larger quantities, with the same chemistry and QC
Choice of modification chemistry: we offer a broad range of oligonucleotide synthesis capabilities, including backbone, sugar and conjugation chemistries, enabling the development of modified oligonucleotides tailored to specific research and therapeutic applications
Duplex melting (Tm) characterisation: experimentally determined affinity for complementary RNA, because nearest-neighbour prediction models break down once sequences carry modifications

Modification chemistry

Three key elements shape the performance of a therapeutic oligonucleotide in vivo: sugar chemistry, backbone chemistry and conjugation. At Assemblon, we offer a broad range of options across all three. The examples below highlight some of our capabilities and are not exhaustive.

Sugar modifications

DNA, RNA, 2′-OMe, 2′-F, FANA, 2′-MOE, LNA, cEt, 2′-NMA and TNA. These change how tightly a strand binds its target and how well it resists nuclease degradation.

Backbone modifications

Phosphodiester (PO), phosphorothioate (PS), phosphorodithioate (PS2), methylphosphonate (MeP), phosphoramidate (PA) and mesyl phosphoramidate (MsPA). Backbone chemistry is usually the single biggest driver of an oligonucleotide's stability in serum and tissue.

Conjugates and terminal modifications

We offer a range of conjugation and terminal-modification chemistries, including GalNAc, cholesterol, palmitate and 5′-(E)-vinylphosphonate. These modifications influence cellular uptake, tissue distribution, pharmacokinetics and other properties that are critical to the performance of therapeutic oligonucleotides in vivo.

Modifications

DNA

Standard deoxyribose, the unmodified reference chemistry

RNA

Standard ribose, native to endogenous RNA pathways

2′-OMe

Methyl at the 2′-OH, a common nuclease-resistance modification

2′-F

Fluorine at the 2′ position, favours A-form (RNA-like) duplex geometry

2′-MOE

Methoxyethyl at the 2′, the gapmer-wing chemistry behind most approved ASOs

LNA

2′,4′-bridged "locked" sugar, a large affinity (Tm) boost per residue

cEt

Constrained ethyl bridge, LNA-like affinity, different tolerability profile

2′-NMA

2′-O-N-methylacetamide, shown to enhance splicing modulation activity in antisense oligonucleotides

TNA

Threose nucleic acid, a four-carbon threose in place of ribose, valued for its exceptional nuclease resistance

Built for your modality

Antisense oligonucleotides

Single-stranded oligonucleotides that act on a target mRNA by RNase H-mediated degradation (typically a gapmer, a central DNA block flanked by modified RNA wings), by steric blocking of translation, or by modulation of splicing. Fomivirsen, the first approved oligonucleotide drug, used the RNase H route.

Splice switching

Oligonucleotides that work inside the nucleus, redirecting pre-mRNA splicing to include or exclude a targeted exon and restore a functional reading frame. Nuclear localisation, not just target binding, is what makes this mechanism work.

siRNA

Double-stranded oligonucleotides that load into Argonaute2 as part of RISC, using the guide strand to direct sequence-specific cleavage of a complementary mRNA. GalNAc conjugation for hepatocyte targeting and lipid nanoparticle formulation took siRNA from concept to approved drug class.

miRNA

Mimics and inhibitors (antagomirs) of endogenous microRNAs, used to restore or suppress a regulatory pathway rather than knock down a single transcript.

CRISPR guide RNAs

Synthetic sgRNAs and crRNAs that direct Cas nucleases to a genomic target, where terminal chemistry matters for both stability and reduced immunogenicity.

Aptamers

Single-stranded oligonucleotides selected to fold into a defined three-dimensional structure and bind a protein target directly, closer to a chemical antibody than a hybridisation mechanism. Pegaptanib, the first approved therapeutic aptamer, relied on 2′-fluoro and 2′-OMe chemistry to hold that fold together.

Whatever the modality, the question is the same: does this sequence, with this chemistry, do what you need it to do in vivo? That is what we help you answer.

Quality

Every modified oligonucleotide we make undergoes UPLC-MS analysis prior to release, irrespective of scale or project timeline. We can also develop bespoke analytical methods to meet the specific requirements of your oligonucleotide and provide comprehensive characterisation. Our analytical workflows are designed to support rapid turnaround without compromising quality or analytical rigour. See Quality.

A partner throughout your programme

Oligonucleotide design and chemistry should be carefully considered to identify and address potential challenges before they become costly. We support researchers from initial chemistry considerations through oligonucleotide synthesis, purification and analysis, helping translate promising designs into well-characterised experimental materials. Our expertise can help identify practical challenges early and accelerate progression to downstream research.

Built on Oxford chemistry

Assemblon was co-founded by Emeritus Professor Tom Brown of the University of Oxford. He has published almost 500 research papers and patents in the nucleic acid field and has received several awards, including the Royal Society of Chemistry Josef Loschmidt Prize, the RSC Prizes for Nucleic Acid Chemistry and Interdisciplinary Research, the Khorana Prize, BBSRC Innovator of the Year and Chemistry World Entrepreneur of the Year.

His group's contributions to oligonucleotide chemistry underpin Assemblon's approach to modified oligonucleotide synthesis and functionalisation.

Talk to us

Send us the sequence and one of our experts will tell you whether it is feasible, what it will cost and how long it will take, before you commit.

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