How ‘Delivery Enabled’ oligotherapeutics can change the landscape of disease and treatment

It is well within living memory that the real function of DNA, RNA and the ‘central biological dogma’ was understood and clarified (do read Lessons in Chemistry). This advancement in core biological understanding has led many to identify new routes to intervening in complex disease states – none more fundamental than the control of DNA identity, epigenetic interactions and the transcription/translation processes.

Though not a ‘rewriting’ of the genetic code, manipulation of transcription/translation constitutes an extremely early biological intervention. The nature of DNA/RNA as a restricted code-based polymer also enables the strongest form of selectivity compared to molecules interacting with flexible proteins and cell receptors (i.e. any 17mer oligonucleotide sequence is expected to only occur once in the human genome).[1] However, if oligotherapies have the programmable capacity to specifically treat any disease, why is there not a therapy for everything?

After improving the chemical manufacturing process of oligo materials in the mid-1980s there was a concerted effort to improve oligonucleotide stability and therapeutic potential. The application of new chemistries to protect the oligo backbone (phosphorothioate, morpholino, locked…) were mixed with 2′- OH modifications (2′-OMe, 2′-F, 2′-MOE…) to produce therapies which could survive the harsh environments within the body. These combined with new strategies to target sequences, such as gapmers (a DNA core flanked by RNA mimics) and splice site switching (control of natural RNA sequence determination) produced a toolbox of reagents and methods to develop into world changing therapies.[2] But still there was a problem – the delivery of these materials was often so poor that there was no clinical benefit seen when translating from the bench to the clinic (Figure 1.).[3]

Figure 1. Comparison of the number of investigational new drug (IND) applications with FDA approval of oligotherapies. Upon the beginning of the fields clinical expansion there was little uptake in the new modality and very few approved therapies. However, new delivery and targeting chemistries changed this in the mid-2010s with a larger number of approvals and investigations into new diseases reigniting the field and clinical possibilities.  

It took two breakthroughs in delivery to reignite the promise of oligonucleotide therapeutics – tri GalNAc conjugates (sugar molecules which target the liver) and lipid nanoparticles (ball-like packages which protect and hide oligo-cargo).[4] These relatively simple advances gave oligotherapeutics a springboard and the COVID-19 pandemic saw their highly effective application globally.

With the key methodology validated we are now reaching into the future, looking to get more oligotherapeutics into harder to reach areas of the body at effective concentrations.[5] This quest for innovation and need for better access to complex tissue types has driven TargoPep and its current research programme. With the design of an oligotherapeutic, even with its modifications and intricacies reduced down to a set of codified rules and outcomes, focus on formulation and delivery is the next hurdle that, when solved, could revolutionise our approach to addressing previously untreatable diseases.

[1] Egli, M., Manoharan, M. NAR 2023, 51, 2529–2573.

[2] Kulkarni, J.A., Witzigmann, D., Thomson, S.B., Chen, S., Leavitt, B.R., Cullis, P.R., Van der Meel, R. Nat. Nanotechnol. 2021, 16, 630-643.

[3] High, K.A. Nat. Comm. 2020, 11, 5821.

[4] Roberts, T.C., Langer, R., Wood, M.J.A. Nat. Rev. Drug Discov. 2020, 19, 673–694.

[5] Corey D.R., Damha, M.J., Manoharan, M. Nucleic Acid Ther. 2022, 32, 8-13.

Dr Fergus McWhinnie February 2024