Harnessing nuclear delivery to boost antisense oligonucleotide efficacy
NATA have contributed to a new study exploring a novel way to enhance the effectiveness of antisense oligonucleotide (ASO) therapies. This project, in collaboration with UCL, demonstrates how modifying ASOs to improve their delivery to the nucleus can significantly enhance their therapeutic potential, offering new opportunities for both current and previously trialled treatments.
Antisense oligonucleotides (ASOs) are a powerful class of nucleic acid therapies that can alter gene splicing or degrade incorrect RNA species to modify disease processes. However, both these mechanisms occur inside the cell nucleus. Therefore, to be effective, ASOs need to both enter and remain in the nucleus; this is something that has proven challenging to achieve consistently.
In a new study led by Disha Kashyap from the Booth Research Group at the University of Oxford and UCL, researchers tackled this challenge by attaching ASOs to the small molecule (+)-JQ1. This molecule binds tightly to BET bromodomain proteins, which shuttle naturally between the cytoplasm and nucleus. By “hitching a ride” on this trafficking system, the modified ASOs accumulate more efficiently in the nucleus, resulting in stronger therapeutic effects.
The team tested this strategy across different types of ASOs and disease-relevant targets. Splice-switching ASOs conjugated with (+)-JQ1 demonstrated up to twice the activity of their unmodified counterparts, restoring proper RNA splicing in cell models. Similarly, RNase H-active ASOs targeting the cancer-associated RNA MALAT-1 achieved faster and more robust knockdown when modified with (+)-JQ1. Immunocytochemistry carried out by NATA also confirmed that the enhanced nuclear accumulation drives the increased potency of (+)-JQ1-conjugated ASOs.
Figure reproduced from: Kashyap, Disha, et al. Harnessing Bet-Bromodomain assisted nuclear import for targeted subcellular localization and enhanced efficacy of antisense oligonucleotides. Journal of the American Chemical Society, vol. 147, no. 32, pp. 29478–29488 (2025), https://doi.org/10.1021/jacs.5c09544.
Researchers also applied this approach to Oblimersen, an ASO drug targeting BCL-2 that had previously failed in Phase III cancer trials despite being safe in patients. Remarkably, the (+)-JQ1-Oblimersen conjugate showed significantly greater activity and chemosensitisation in leukaemia cell models, suggesting that this therapeutic could be worth revisiting.
This study highlights the importance of precise subcellular targeting for nucleic acid medicines. By ensuring that a larger proportion of ASOs reaches the nucleus, this can enhance their activity and therapeutic potential. The approach is modular, meaning it could be applied to different ASOs, chemistries, and disease targets, and may even revive older drug candidates that underperformed in previous trials.
Read the publication: Harnessing BET-Bromodomain Assisted Nuclear Import for Targeted Subcellular Localization and Enhanced Efficacy of Antisense Oligonucleotides | Journal of the American Chemical Society