Oligos Step Into The Spotlight: A Growing Force In Genetic Medicine

By Carl Schoellhammer, DeciBio Consulting

Once seen as a niche modality, oligonucleotide therapeutics have emerged as validated, revenue-generating platforms with clear clinical utility and room to grow.

Over the past decade, the field has moved well beyond early proof-of-concept programs. Today, it boasts a growing list of approved therapies with real commercial traction: Biogen’s Spinraza; Alnylam’s Onpattro, Oxlumo, and Amvuttra; Ionis’s Tegsedi, Qalsody, and Wainua; Novartis’ Leqvio; Novo Nordisk’s Rivfloza; NS Pharma’s Viltepso; and Sarepta’s Exondys 51 and Amondys 45, among others. Collectively, these products bring in billions of dollars in annual revenue and offer important therapeutic options for patients across rare and more common diseases.

The field is also experiencing a new wave of momentum. Investor interest has ramped up, new companies are launching, and large biopharma players are inking strategic partnerships. Perhaps most notably, oligo-based strategies are expanding beyond gene silencing into emerging approaches like RNA editing and splicing modulation to offer a fuller menu of ways to tune gene expression. As the science evolves and the market opportunity expands, the oligonucleotide therapeutics landscape is poised for continued growth and diversification.

Oligos Are Here to Stay

One of the core advantages of oligonucleotides is that they work. The mechanisms are well understood and reliably deliver the desired pharmacological effect. Their manufacturing is also relatively straightforward compared to large biologics or complex cell therapies, and improvements in formulation and chemical stabilization have dramatically extended their durability in the body.

Delivery, which is often a major barrier for nucleic acid-based drugs, has made significant advancements in certain tissues. Hepatic delivery has become a non-issue thanks to the widespread adoption of GalNAc conjugation, which enables precise and efficient targeting to the liver. This breakthrough has unlocked a wave of clinical development focused on liver-expressed targets.

While many early oligo drugs targeted rare diseases (Spinraza for spinal muscular atrophy, Onpattro for hereditary ATTR amyloidosis, Tegsedi for polyneuropathy) one product marked a pivotal shift: Inclisiran.

Originally developed by Alnylam and later acquired by The Medicines Company (and eventually Novartis), Inclisiran is a GalNAc-conjugated siRNA targeting PCSK9, a liver gene implicated in cholesterol regulation. With a twice-yearly dosing schedule after initial loading, the drug treats hypercholesterolemia with the convenience of infrequent administration and a clear molecular rationale. Blackstone’s $1 billion investment in 2020 to acquire half of Alnylam’s royalty stream on Inclisiran underscored the sky-high expectations for this program.

Inclisiran demonstrated that oligo-based therapies can go beyond rare disease and into primary care markets with scalable manufacturing and differentiated pharmacokinetics. With delivery to the liver de-risked and durability proven, the door is now open for a broader application set across common diseases.

A Shift Toward Cardiometabolic And CNS Indications

Building on the success of liver-targeted drugs like Inclisiran, developers are now pushing the modality into new therapeutic areas, most notably cardiometabolic diseases and central nervous system (CNS) disorders. Recent clinical milestones and deal-making activity suggest this shift is well underway.

In the cardiometabolic realm, Ionis announced positive topline data for Olezarsen in patients with moderate hypertriglyceridemia, an increasingly prevalent condition associated with cardiovascular risk. This builds on Olezarsen’s late 2023 FDA approval for familial chylomicronemia syndrome. Meanwhile, Lilly similarly reported positive results for Lepodisiran, an siRNA that reduced lipoprotein(a) levels by over 90% in a Phase 2 study. These medicines could be important medicines to add to the therapeutic armamentarium for lowering cardiac risk factors.

On the CNS front, Atalanta Therapeutics raised a $97 million Series B to advance RNAi therapies for neurological diseases, while Biogen entered a partnership with City Therapeutics to combine its delivery technology with the latter’s siRNA platform for CNS indications. This speaks to growing confidence in both the pharmacological potential and delivery feasibility of oligos across the blood-brain barrier.

Beyond these headline deals, a host of players are actively expanding the oligo toolkit for metabolic and neurological conditions. Companies like Sirnaomics, Arrowhead Pharmaceuticals, Haya Therapeutics, Stoke Therapeutics, Silence Therapeutics, Novo Nordisk (via legacy Dicerna assets), and Roche are all investing in next-generation oligo pipelines. Even pharma giants are taking notice: AbbVie recently announced a collaboration and license agreement with ADARx Pharmaceuticals to develop next-gen siRNA therapeutics across multiple therapeutic areas and, most recently, Avidity Biosciences was the subject of M&A speculation with its stock jumping ~30% on rumors of a Novartis takeover, another clear signal that major players are eager to secure a foothold in the oligo space.

Enabling Tools Ecosystem Also Maturing

As oligonucleotide drugs evolve beyond rare disease and address broader applications, the supporting ecosystem of enabling tools has become both the unsung hero and the emerging bottleneck. In recent advisory board discussions and expert interviews, many stakeholders emphasized that technical innovation across delivery, chemistry, screening, and manufacturing is no longer just supportive infrastructure. It’s increasingly the main driver of what the modality can achieve next.

Delivery: Beyond The Liver

With GalNAc conjugation largely solving hepatic delivery, attention has shifted toward solving delivery in harder-to-reach tissues such as the central nervous system, muscle, lung, and solid tumors. As several KOLs DeciBio spoke to as part of our recent advisory board on oligonucleotide drugs succinctly put it: “The liver is solved — everywhere else is the challenge of the decade.”

Emerging strategies range from antibody- and peptide-oligo conjugates for cell-specific targeting to exosome-based carriers and optimized synthetic polymers. In the CNS, approaches like intrathecal administration and receptor-mediated blood-brain barrier crossing are under active exploration, but none have yet emerged as a universal solution. For now, many in the field remain cautious as non-conjugated, systemically delivered oligos continue to face steep challenges outside the liver.

Chemistry: Stretching The Limits

First-generation chemistries enabled the early wave of approvals, but many stakeholders believe the current modification toolkit is nearing its ceiling. There is growing demand for novel backbones and conjugates that can improve nuclease resistance, enhance pharmacokinetics, and reduce immunogenicity, all without adding unsustainable synthetic complexity.

KOLs across the field cite interest in hybrid backbones (e.g., phosphorothioate-boronophosphate), locked nucleic acids (LNAs), advanced methylations, and multifunctional conjugates. Dual-purpose modifications, such as tissue targeting plus endosomal escape features, are especially promising, potentially marking the next major inflection point for the use of oligonucleotides outside the liver.

Screening And Analytics: Complexity Requires Clarity

As oligonucleotides become more chemically and biologically complex, discovery platforms are under increasing pressure to deliver deeper insights earlier in development. Structure-activity relationship screening is now table stakes; what’s needed are tools that can dissect cellular uptake, intracellular trafficking, endosomal escape, and metabolic stability, all areas where the knowledge gap remains wide.

High-content in vitro systems and organ-on-chip platforms are beginning to fill that void, particularly for CNS and metabolic targets. Still, predictive models for pharmacokinetics, pharmacodynamics, and immunogenicity remain underdeveloped. KOLs highlighted AI- and ML-enabled analytics, as well as robust high-throughput quality control, as key investment areas for the next generation of discovery infrastructure.

Manufacturing: Scaling The Modality

Nowhere is the shift toward mainstream medicine more tangible or tested than in manufacturing. Purification remains a widely cited pain point across industry KOLs, often emerging as the critical gating factor for scale. Supply chain strain, raw material variability, and increasing demands for analytical rigor only add to the pressure.

Automation and continuous manufacturing are gaining ground, though most KOLs across the industry see progress here as evolutionary rather than transformative as of now. Enzymatic synthesis, with its potential to generate longer, purer oligos via greener and more scalable methods, holds promise but isn’t yet widely deployed for therapeutic production. As CDMOs take on increasingly complex programs, their ability to provide in-process analytics, responsive documentation, and close customer engagement is becoming a decisive differentiator. In many cases, trust and transparency now matter as much as technical capability.

Integration And Outlook: Infrastructure Meets Strategy

The tools ecosystem supporting oligonucleotide therapeutics is steadily moving toward deeper integration, standardization, and digitalization. Vertical integration is on the rise, driven by a need to manage risk and control quality. Real-time digital quality control and regionally diversified supply chains are no longer optional: they’re strategic imperatives for sustainable commercial execution.

As oligos expand into higher-volume indications like cardiometabolic disease, CNS disorders, and oncology, the infrastructure supporting them must evolve in parallel. The consensus across the field is clear: the next wave of progress won’t just be about new targets or novel mechanisms, it will hinge on how well we deliver, manufacture, and de-risk these increasingly sophisticated molecules. What was once background infrastructure is now moving to center stage.

Conclusion: From Niche To Necessary

Oligonucleotide therapeutics have moved beyond proof-of-concept. With validated mechanisms, commercial traction, and a growing list of indications, they’re no longer a niche experiment. They’re a core part of the genetic medicine arsenal. But the path forward isn’t automatic. Continued progress will hinge on expanding delivery beyond the liver, upgrading the chemistry toolbox, and modernizing the tools that support discovery and scale.

As the field sets its sights on larger patient populations and more complex diseases, success will depend on how boldly and collaboratively we tackle these next-phase challenges. For researchers, investors, and innovators alike, now is the time to double down on not only the programs but on the infrastructure that will power the next generation of oligo breakthroughs.

About The Author

Carl Schoellhammer, Ph.D., is a partner at DeciBio Consulting, where he leads the advanced therapies practice. He specializes in advising clients across drug development, manufacturing and bioprocessing concerns, pipeline optimization, and opportunity assessments. He previously founded Suono Bio, a venture-backed biotech from the lab of Prof. Robert Langer at MIT. Schoellhammer holds a Ph.D. from MIT.