Oligonucleotide Therapeutics At Scale: Bottlenecks, Breakthroughs, And What Comes Next

A conversation with William Soliman, Ph.D., BCMAS, founder & CIO, White Manna Capital

As RNA therapeutics continue to mature, oligonucleotides occupy a uniquely proven yet persistently constrained corner of the field. Antisense and RNA interference drugs have delivered some of RNA medicine’s earliest clinical and commercial successes but scaling these therapies beyond rare diseases has exposed fundamental challenges in manufacturing, delivery, and regulatory alignment.

In this Q&A with Life Science Connect Acquisition Editor Michael Soloway, William Soliman, Ph.D., BCMAS — founder and CIO of White Manna Capital — offers a candid perspective on what is truly limiting oligonucleotide therapeutics today, what chemistry and delivery innovations have already changed the equation, and where the most credible near-term opportunities lie. From CMC realities to platform strategy, this conversation explores what it will take for oligonucleotides to move from precision tools to broadly scalable medicines.

Advancing RNA (ARNA): What is the biggest scientific or manufacturing bottleneck facing oligonucleotide therapeutics today — and why hasn’t it been solved yet?

WS: The most significant bottleneck facing oligonucleotide therapeutics today remains manufacturing scale and cost, particularly as programs move beyond rare diseases into larger patient populations. While the science behind antisense oligonucleotides (ASOs), siRNA, and related modalities has matured substantially, the ability to reliably and economically produce full-length, high-purity oligonucleotides at commercial scale continues to lag behind clinical ambition.

At the heart of this challenge is the reliance on solid-phase oligonucleotide synthesis, a chemically intensive, stepwise process that becomes increasingly inefficient as sequence length increases. Each nucleotide addition introduces yield loss, impurity risk, and solvent consumption. When manufacturing short oligos for ultra-rare indications, these inefficiencies are manageable. However, when companies attempt to supply therapies for thousands — or potentially hundreds of thousands — of patients, the limitations become acute.

In addition to synthesis inefficiencies, oligonucleotide manufacturing requires specialized facilities, highly controlled environments, and access to large volumes of high-purity solvents and reagents. Solvent supply chains, in particular, have emerged as a non-trivial constraint, both from a cost and sustainability standpoint. Unlike biologics, where cell lines can be scaled in large bioreactors, or mRNA, which benefits from enzymatic amplification, oligonucleotides scale linearly — more drug requires proportionally more chemistry, solvent, and time.

This problem has not yet been fully solved because there is no disruptive manufacturing paradigm currently capable of replacing solid-phase synthesis at scale. While solution-phase synthesis and enzymatic approaches are being explored, they are not yet validated for GMP production of complex modified therapeutic oligos. As a result, the field remains constrained not by scientific feasibility but by the industrial physics of chemical manufacturing, which has proven slow and expensive to transform.

ARNA: How are advances in oligo chemistry (e.g., backbone, sugar, or base modifications) changing clinical performance or safety profiles?

WS: Advances in oligonucleotide chemistry have been one of the most important drivers of clinical success in the field over the past two decades. Early oligonucleotide drugs suffered from rapid degradation, poor tissue retention, and unacceptable immunostimulation. Modern backbone, sugar, and base modifications have fundamentally changed that equation.

Backbone modifications such as phosphorothioate (PS) linkages significantly improve nuclease resistance and plasma protein binding, enabling longer circulation times and improved tissue uptake. Sugar modifications, including 2′-O-methyl, 2′-O-methoxyethyl (2′-MOE), and locked nucleic acids (LNAs), further enhance stability, binding affinity, and target engagement. These chemical refinements allow lower doses to achieve therapeutic effect, which in turn improves safety margins.

Collectively, these modifications translate into improved clinical efficacy with reduced off-target toxicity. Enhanced binding affinity enables shorter oligos or lower dosing, reducing unintended hybridization events. Improved stability reduces the formation of degradation products that could otherwise contribute to immune activation or organ toxicity.

Importantly, these advances also enable chimeric oligonucleotide designs, in which different chemical motifs are strategically placed along the sequence to balance potency, distribution, and tolerability. This rational chemical engineering approach has transformed oligonucleotides from fragile research tools into clinically viable therapeutics with increasingly predictable safety profiles.

ARNA: From a CMC perspective, what makes tech transfer or GMP scale-up uniquely challenging for oligonucleotide therapies compared to mRNA or biologics?

WS: From a chemistry, manufacturing, and controls (CMC) standpoint, oligonucleotide therapies present a unique and often underappreciated set of challenges. Unlike biologics, which rely on living systems, or mRNA, which is produced enzymatically, oligonucleotides are chemically synthesized, heavily modified polymers, each with a distinct impurity and analytical profile.

Tech transfer for oligonucleotides requires highly specialized analytical methods capable of resolving closely related species, including truncated sequences, depurinated products, backbone variants, and modification-specific impurities. Small changes in synthesis conditions, resin quality, or reagent purity can meaningfully alter impurity profiles, making process reproducibility across sites difficult.

Solid-phase synthesis also introduces logistical and regulatory hurdles. Solvent volumes scale rapidly, increasing environmental, safety, and compliance burdens. Equipment capacity becomes a limiting factor, as synthesis columns and purification systems cannot be scaled indefinitely without compromising performance.

In contrast, mRNA manufacturing benefits from enzymatic amplification and relatively uniform molecular structures, while biologics leverage decades of regulatory precedent in cell-based production. Oligonucleotide manufacturing sits in an uncomfortable middle ground — neither biologic nor small molecule — requiring bespoke regulatory strategies and close alignment with health authorities to define acceptable controls, specifications, and comparability frameworks.

ARNA: What lessons from approved oligonucleotide drugs are still being overlooked by companies entering the space today?

WS: Despite more than two decades of clinical experience, several critical lessons from approved oligonucleotide drugs remain insufficiently internalized by new entrants to the field. One of the earliest examples is fomivirsen, the first FDA-approved antisense oligonucleotide, approved in 1998 for cytomegalovirus (CMV) retinitis in AIDS patients.

Although fomivirsen was ultimately withdrawn — not due to safety or efficacy failures, but because highly active antiretroviral therapy (HAART) dramatically reduced CMV retinitis incidence — it nonetheless demonstrated that targeted mRNA inhibition could be clinically viable. Importantly, its development highlighted early challenges around stability, delivery, and immunogenicity that remain relevant today.

Subsequent oligonucleotide programs have reinforced the importance of early chemical modification, rather than retrofitting stability or tolerability fixes late in development. Programs that delay optimization of backbone chemistry, impurity control, or delivery strategy often encounter late-stage setbacks that could have been avoided with a more integrated design approach.

Another overlooked lesson is the necessity of co-developing delivery and drug substance, rather than treating delivery as a downstream add-on. Finally, approved oligonucleotide drugs underscore the need for rigorous impurity control strategies, as even low-level sequence variants can have outsized biological effects. Companies entering the space today often underestimate how early these considerations must be embedded to ensure long-term success.

ARNA: How do delivery strategies (GalNAc, conjugates, LNPs, others) influence development timelines and regulatory risk for oligo programs?

WS: Delivery strategy is arguably the single most important determinant of development speed and regulatory risk in oligonucleotide programs. The emergence of GalNAc conjugation has been transformative, particularly for liver-targeted indications. By exploiting the asialoglycoprotein receptor on hepatocytes, GalNAc enables efficient, selective uptake with subcutaneous dosing and minimal systemic exposure.

As a result, GalNAc-based programs often progress five to seven years faster than comparable extrahepatic programs, benefiting from well-established regulatory precedents, predictable pharmacokinetics, and favorable safety profiles. For liver indications, GalNAc is now considered a low-risk, platform-validated approach.

In contrast, extrahepatic delivery remains more complex. Lipid nanoparticles (LNPs), antibody-oligonucleotide conjugates (AOCs), and other targeting strategies have shown promise, but they introduce additional CMC and immunogenicity risks. Particle size distribution, stability, and batch-to-batch consistency become critical regulatory considerations, often adding one to two or more years to development timelines.

While these approaches are necessary to unlock broader disease areas, they demand greater up-front investment, deeper regulatory engagement, and more conservative development planning compared to mature GalNAc-liver programs.

ARNA: Where do you see the most near-term clinical or commercial opportunity for oligonucleotides in the next two to three years — and why?

WS: In the near term, the most compelling clinical and commercial opportunities for oligonucleotides lie in central nervous system (CNS) disorders and neuromuscular diseases, including muscular dystrophies. These areas have already demonstrated willingness from regulators, payers, and patients to support high-value precision therapies.

The commercial success of Spinraza (nusinersen) in spinal muscular atrophy stands as a defining proof of concept, generating multibillion-dollar revenues while validating intrathecal oligonucleotide delivery. Building on this foundation, next-generation chemistries and improved targeting strategies are expanding the addressable CNS landscape.

Moreover, advances in antibody-oligonucleotide conjugates are enabling more precise extrahepatic targeting, accelerating pipelines and driving significant licensing and partnership activity. Over the next two to three years, this convergence of clinical validation, technological maturity, and unmet medical need is likely to fuel substantial commercial growth.

ARNA: What misconceptions about oligonucleotide therapeutics still persist among investors, regulators, or the broader RNA field?

WS: One of the most persistent misconceptions surrounding oligonucleotide therapeutics is the belief that manufacturing speed and chemistry maturity alone guarantee success, while delivery remains an afterthought — particularly for extrahepatic tissues. In reality, delivery remains the primary rate-limiting step for many programs.

Another challenge is regulatory misalignment. Oligonucleotides are often evaluated through inappropriate regulatory frameworks borrowed from biologics or small molecules, complicating CMC expectations and comparability assessments. This mismatch can slow development and increase perceived risk.

Finally, oligonucleotides continue to be undervalued relative to mRNA in some investment circles, despite offering superior gene-silencing precision, longer durability, and expanding tissue reach. As delivery technologies mature and more programs achieve late-stage success, this perception gap is likely to close — but it remains a barrier today.

About The Expert

William Soliman, Ph.D., is the founder & CEO of the Accreditation Council for Medical Affairs (ACMA) and the founder & CEO of White Manna Capital Partners, a biotech/pharma focused hedge fund. The ACMA is the leading life sciences accreditation, certification, and training company in the world and established the first ever certification standards for prior authorization, reimbursement, pharma sales, medical science liaisons, and medical affairs professionals.

Soliman is considered a pharmaceutical industry futurist. In March 2021, he testified before the United States Congress’ Energy and Commerce Health Subcommittee about the pharmaceutical industry and the importance of professional standards for those who directly engage healthcare providers, like sales representatives. Soliman is a former pharmaceutical executive who held leadership roles at several big pharma companies including Merck, Johnson & Johnson, AbbVie, and Gilead.

He is routinely featured on media outlets such as NewsNation, Fox News, ABC News, Forbes, Al Jazeera, Yahoo! Finance, Yahoo! Business TV, and more. Soliman received his Ph.D. from Columbia University and his bachelor’s degree from New York University.