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Breakthrough in siRNA Stability and Efficacy for Therapeutics
A recent study led by Ken Yamada, Ph.D., and Anastasia Khvorova, Ph.D., has unveiled a significant advancement in the stability and effectiveness of oligonucleotide therapeutics. Their research, published in Nature Biotechnology, highlights a promising approach that could extend the applications of small interfering RNAs (siRNAs) beyond the liver, potentially opening new avenues for treating various diseases.
“The key innovation in our research lies in a modification to the chemical architecture of the oligonucleotide platform,” stated Dr. Khvorova, who holds the Remondi Family Chair in Biomedical Research and serves as a professor of RNA therapeutics.
The team discovered that by adding single carbon atoms to the RNA backbone, the lifespan of oligonucleotides in cellular environments can be significantly prolonged. This modification helps to protect these molecules from nucleases—enzymes that typically degrade oligonucleotides—allowing them to remain active longer. “Such modifications are essential for the success of oligonucleotide drugs as a therapeutic category,” she added.
Oligonucleotide drugs represent a novel class of treatments designed to modulate the expression of genes associated with diseases. Currently, the FDA has approved six siRNAs, all for use in the liver, with additional candidates undergoing late-stage clinical trials. The initial siRNA, patisiran, marketed as Onpattro, received approval in 2018 for treating hereditary transthyretin-mediated amyloidosis, a rare liver condition.
Despite their therapeutic promise, oligonucleotides are inherently unstable, with nucleases rapidly degrading them within living cells, thus limiting their therapeutic effectiveness. This instability has prompted researchers to explore various chemical modifications aimed at enhancing the durability of these drugs.
Traditionally, modifications have concentrated on adjusting phosphorothioates or sugar components in the oligonucleotide backbone. However, Dr. Yamada and Dr. Khvorova shifted their focus to the carbon components of the chemical structure. According to Dr. Yamada, “In natural systems, small modifications such as methylation can lead to significant changes in the function of DNA and proteins,” highlighting that it is often minor structural tweaks that yield major cellular impacts.
In their experiments, the researchers identified that inserting an additional carbon atom at a specific location in the nucleoside’s structure effectively shielded the oligonucleotide from nuclease degradation, resulting in the development of a new variant termed extended nucleic acid (exNA). This modified oligonucleotide demonstrated a remarkable 32-fold increase in cellular persistence compared to traditional phosphorothioate versions.
“The positioning and manner in which carbon is added are crucial,” Dr. Yamada noted. “Even subtle structural alterations, when properly executed, can dramatically influence the efficacy of these therapeutics.” He further emphasized the implications of their findings, stating that such increases in persistence could transform dosing schedules, potentially reducing treatment frequency from every two weeks to every five months, which could significantly enhance patient compliance and therapy outcomes.
Dr. Khvorova expressed optimism about the applicability of their findings to a broader range of tissues and conditions, saying, “The potential to target diseases in the muscle, kidney, central nervous system, pancreas, and eye is now within reach, expanding the horizons for oligonucleotide therapies.”
The forthcoming stage of their research will involve assessing the safety and longevity of the modified oligonucleotide backbone in clinical trials, paving the way for new therapeutic strategies in the future.
More information: Ken Yamada et al, Enhancing siRNA efficacy in vivo with extended nucleic acid backbones, Nature Biotechnology (2024). DOI: 10.1038/s41587-024-02336-7
This research emphasizes the critical role these modifications play in developing effective oligonucleotide-based therapeutics, ushering in new potential for treating a variety of diseases previously deemed challenging to target.
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phys.org