OLIGONUCLEOTIDE THERAPEUTICS
Where are we and what lies ahead
Dr. Arijit Bhowmick, Director and Head of Oligonucleotide Therapeutics Drug Discovery, Insitro
This Q&A explores the evolving landscape of oligonucleotide and RNA therapeutics, covering advances in siRNA, ASO, and aptamers, delivery challenges, chemical innovations, and AI applications. The discussion also highlights preclinical strategies, investment considerations, and future directions shaping the next decade of small RNA medicines across diverse therapeutic areas.
1. Over the past decade, how have you seen the field of oligonucleotide and RNA therapy evolve, particularly in terms of clinical translation and real-world impact?
I think the past decade truly represents a watershed moment for oligo therapeutics! We witnessed the dramatic maturation of oligonucleotide design, chemistry and delivery technologies (particularly in the liver), which led to the approval of several (~19) drugs by FDA/EMA, and propelled development activities of many other drugs across disease areas and indications. Oligonucleotides have allowed for the targeting of disease-causing proteins that had been previously considered "undruggable" by conventional modalities [up until now]. Crucial advancements in design, synthesis, and CMC have accelerated development timelines compared to traditional drug discovery. The field has now reached a key inflection point, having addressed challenges in stability, delivery, and safety, as evidenced by the number of oligo therapy programs now underway. This, I think, is an incredible achievement for a field that can still be considered fairly “young” as compared to more traditional therapeutics such as small molecules or antibodies.
There is a concurrent rise in realworld evidence (RWE) of efficacy and safety for this class of drugs. Spinraza, one of the early approved oligo therapies for SMA, has shown a favorable safety and efficacy profile in patients on treatment for 3-5 years. For the exon skipping oligos in DMD, initial trials have shown favorable safety and efficacy based on surrogate end points. Another disease space where we have seen multiple siRNA/ASO trials and approvals is hATTR (Hereditary Transthyretin Amyloidosis). Liver targeting Galnac technology has revolutionised treatment approaches for hATTR, with the ability of targeting the TTR mRNA precisely in the liver. hATTR siRNAs have shown encouraging safety and durability in trials. On the other hand, Inclisiran, an siRNA drug for hypercholesterolemia, represents a paradigm shift in the management of a major public health issue using an oligo therapy. The extensive ORION clinical trial program, involving thousands of patients with atherosclerotic cardiovascular disease demonstrated that inclisiran can be administered twice yearly, maximising patient adherence to the drug. Overall, the data from clinical trials and RWE of oligo therapies in the past decade have established oligonucleotides as a safe, effective, and durable class of drugs, which are poised to move from rare disease space to a larger population.
2. Among siRNA, ASO, and Aptamer modalities, which do you think holds the most promise for treating complex diseases, and why?
I think we can’t really say if one modality will be the winner across all complex diseases. It depends on the disease, the target and the tissue where it is expressed, dosing requirements, etc. While siRNAs and ASOs have been most successful across several disease areas, aptamers also have their unique advantage when it comes to targeting a protein rather than the gene. However, based on the success of siRNAs and ASOs in liver and CNS, I believe they would continue to make a major impact in these disease areas. Aptamers on the other hand have been successful in the Ophthalmology space, and with advancement in aptamer chemistry and SELEX platforms, could be a major player in that area. Additionally, aptamers can be combined with an siRNA/ASO for precise tissue targeting, which could be a game changer for the field.
3. Could you discuss some novel trends in Aptamer development and their positioning relative to more established modalities like ASOs and siRNAs?
If you look back, Macugen — one of the first approved oligonucleotide drugs — was an aptamer that was approved back in 2004! Then after 20 years we saw the approval of Izervey (avacincaptad pegol intravitreal solution) recently as the second FDA approved aptamer drug. The obvious question is, despite being one of the earliest entrants in the oligo therapy space, why haven’t we seen much activity and more drugs in this space?
I think the answer lies in some of the inherent challenges and issues with classical aptamers and their selection technologies (SELEX). Over the years SELEX technologies have primarily been used for DNA/RNA aptamers and were not optimised for chemically modified aptamer generation, which is crucial for drug development. Post SELEX chemical modification has been challenging, time consuming, and often not very successful. Additionally, classical SELEX methodologies were not equipped to do a deep dive into the sequence space of the aptamer libraries. A lot has changed in the past 10-15 years in this area as well.
Development of HT-SELEX and incorporation of NGS has dramatically improved the ability to fish out more aptamer drug candidates from a selection experiment. Most importantly, innovation to incorporate sugar modifications in aptamers have dramatically enhanced the stability, safety, and durability of these kind of drugs. Modern SELEX platforms have become faster and more robust to quickly identify highly stable and potent aptamers against a protein target. This, coupled with advancements in computational biology tools to carry out sequence clustering, RNA structure prediction, and RNA/protein docking have really brought about a resurgence in the field of aptamer drug discovery. Currently, there is a renewed interest in the industry to develop aptamers as therapeutics in ophthalmology, cancer, inflammation, and anti-coagulation. Also, there is a lot of cutting-edge work ongoing to use aptamers for tissue specific drug delivery of siRNA/ASOs or functionalise LNPs for targeted delivery. The excitement is back! However, I don’t think we can really compare or position aptamers with siRNA/ASOs, since they are very different in their MOAs.
4. What are the biggest scientific or technical bottlenecks currently facing oligonucleotide delivery to specific tissues, especially in extra-hepatic targets?
As you mentioned, extra-hepatic delivery is certainly the key to develop oligo therapies for a wide range of diseases. However, identifying a tissue-specific receptor-ligand pair that can deliver an oligo cargo precisely into the tissue of interest is not trivial. There are several factors that determine successful tissue specific delivery — receptor expression, receptor recycling kinetics and endosomal escape, specificity of the receptor, species translatability, linker chemistry between ligand and cargo — to name a few. Another approach of delivery into extra-hepatic tissue is to use engineered lipids which can enhance tissue tropism away from the liver. In the past few years we have seen significant progress in the area of extra-hepatic delivery, particularly in muscle, kidney, adipose and CNS. Some of these advances have proven to be effective in human clinical trials as well. However, it remains to be seen how these approaches fare in larger trials across disease areas.
Blurb: We have seen several approvals in the last decade, several more are in trials and showing encouraging results so far. The industry in general is more interested in these modalities than ever before. We are seeing oligo therapy programs being initiated either internally or in partnerships across the industry. I think the partnerships and acquisitions in this space in the last few years are a testament of how important oligonucleotides have become as a drug modality, opening up targets that were deemed “undruggable” before. I think the future is very bright and full of opportunities.
5. The chemistry behind oligonucleotide drugs is rapidly advancing. Could you highlight any emerging chemical modifications or scaffold designs that are likely to shape the next generation of oligo therapeutics?
There are several new chemistries and platforms and they all hold a lot of promise! Chemistry innovation has been the pillar for the success of oligo therapeutics. Over several decades advancement in back bone and sugar modifications have made this class of drugs safer, potent and durable in humans. Sugar modifications such as 2’F, 2’OMe, 2’MOE, and back bone modifications such as PS have already been used extensively in FDA approved oligo therapeutics and have been shown to impart incredible stability leading to longer dosing. There are several other modifications which have been shown in the recent past to either improve activity or reduce immunogenicity/tox of oligos. Some of them with promising translatable data are — MsPA backbone modification to improve tox profile of ASOs, stereospecific PN/PS backbone modification to improve stability and potency, addition of GNAs to improve off-target profile, exNA (extended nucleic acid) modification to improve potency and durability, and vP to improve tissue accumulation and potency of siRNAs. One recent example that comes to my mind is the announcement from Biogen regarding the development of Salanersen — a new chemically modified version of Nusinersen (their successful SMA oligo drug), where substitution of 2’OMe with 2’-O-NMA dramatically improved stability and potency, with a possibility of yearly dosing. This, again, shows how innovation in chemistry can continually improve oligo therapeutics. To summarise, the chemistry of oligos is continuously evolving and getting better, and we are seeing exciting new modifications being developed in the field, which will keep making oligonucleotides better, safer, and more potent.
2’F- 2’ Fluoro ; 2’OMe - 2’-O-Methyl ; 2’MOE- 2’Methoxy Ethyl ; PSPhosphorothioate ; PN- phosphoryl guanidine ; MsPA- mesyl-phosphoramidate ; GNA- Glycol Nucleic Acid ; 2’-O-NMA- 2'-O-[2-(methylamino)- 2-oxoethyl] ; exNA- extended nucleic acid ; vP-vinyl phosphonate.
6. How do pre-clinical discovery approaches differ when targeting diseases like neurodegeneration versus cardiometabolic or oncology indications with RNA therapeutics? In your experience, what key parameters define a successful screening and early discovery pipeline for oligonucleotide drugs?
I think pre-clinical discovery approaches generally differ between these disease areas you mentioned, irrespective of the modality. However, particularly for oligos, one has to first understand the delivery challenge for the tissue of interest, before embarking on a drug discovery path. In my opinion, without a well validated delivery method (specific or non-specific) that is translatable, one has to choose a target carefully. If the delivery method is sorted, then the focus should be on developing the best possible molecule. Depending on the modality selection (siRNA/ASO/Aptamer etc) and choice of chemistry, early screening should be designed to screen for efficacy that would possibly lead to meaningful clinical outcome. To that end, developing a TPP for the prospective drug candidate could help. Other crucial parameters at this stage would be to understand the toxicity/off-target profile of selected hits. There are several ways that can be done early on to support DC selection. Another aspect that one should keep in mind while selecting a DC is the dosing requirement (whether only long-term dosing is acceptable or short term dosing is feasible). The dosing requirements in humans can vary significantly between indications and has to be considered early on to design rodent/NHP pk/pd/durability studies. Chemistry optimisation could help achieve high potency and stability, which could in turn affect durability of response and therefore dosing.
7. As someone involved in due diligence for investment decisions, what criteria or red flags do you look for when evaluating new platforms or startups in the oligo space?
I primarily focus on the technical/scientific side of diligence and it is always about data and the right controls! For me the biggest red flag is when proper controls are not used in an in-vitro/ in-vivo study where the aim is to differentiate the platform or the asset from existing platforms or assets in the same disease space. For a novel target, it is crucial to look at the disease relevant outcomes in an in-vivo study, and tolerability of on-target knockdown/inhibition. For new platforms/chemistry I try to dig into the safety, stability, and potency or delivery advantage of the new chemistry/platform over existing ones. Also, in-vitro-in-vivo translation plays an important role particularly for new chemistry platforms.
8. The RNA therapy space has seen notable approvals recently. How do these successes affect industry confidence, and how might they influence partnerships or funding trends? And how do you envision the future of small RNA medicines evolving over the next 5 to 10 years - in terms of technology and therapeutic breadth?
As mentioned earlier, I think this is a great time to be in the oligo therapy space! We have seen several approvals in the last decade, several more are in trials and showing encouraging results so far. The industry in general is more interested in these modalities than ever before. We are seeing oligo therapy programs being initiated either internally or in partnerships across the industry. I think the partnerships and acquisitions in this space in the last few years are a testament of how important oligonucleotides have become as a drug modality, opening up targets that were deemed “undruggable” before.
I think the future is very bright and full of opportunities. The past decade has witnessed the dramatic maturation of oligonucleotide therapeutics and I think this is just the beginning!
The next few years will see extensive innovation in extra-hepatic delivery technologies. With the limited but promising delivery data in muscle and CNS, and innovations in chemistry/conjugates, we can assume that there would be more tissue specific delivery work translated into the clinic. This would lead to development of therapies for a wide range of indications, outside of the liver and CNS. I think the confidence in these classes of drugs is very high and will continue to be so in the coming years.
AI/ML will also continue to have a growing impact in this field as well. They will help identify novel disease relevant targets, and provide deeper insights into disease biology that will eventually help in designing effective oligo therapies like never before. Also, ML based models will keep maturing, eventually helping faster design and discovery of oligo drugs. Lastly, I think we will see increasing oligo therapy programs for more prevalent diseases.
Author Bio
Dr. Arijit Bhowmick oligonucleotide drug discovery and development executive, bringing over a decade of experience in advancing therapeutic pipelines. He has successfully built and led high-performing drug-discovery teams, and established oligonucleotide therapy programs across both emerging biotechs and large pharmaceutical organizations. His expertise spans multiple modalities, including siRNA, antisense oligonucleotides (ASOs), blocking oligos, and aptamers. Currently, he heads oligonucleotide drug discovery at Insitro, working at the intersection of AI/ML and drug discovery. Previously, he held key roles at Regeneron Pharmaceuticals and Vitrisa Therapeutics. In addition to his industry leadership, Dr. Bhowmick also serves as a subject matter expert (SME) and consultant, supporting investor due diligence in the oligonucleotide therapeutics space.
