Tokyo University of Science Research Team Explores Improved Delivery of Antisense Oligonucleotides

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A research team from Tokyo University of Science (TUS) explained in March 2025 that it is exploring ways to improve the delivery of antisense oligonucleotides (ASOs), a class of gene-targeting drugs, to the brain and other organs (1). Led by Professor Makiya Nishikawa, the team is following sustainable development goals (SDGs) put forth by the United Nations (2), particularly improving good health and well-being (SDG 3) and promoting industry, innovation, and infrastructure (SDG 9).

As described in the team’s latest study, published on Feb. 18, 2025 (3), the team delved into the mechanisms that govern the length of time that these compounds remain in the bloodstream, what they bind to, and which tissues they can enter. Getting therapeutic drugs to cross the blood-brain barrier has been a long-time challenge to drug development, as this barrier limits the ability to treat neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease as well as brain cancers. Manipulating gene expression in brain cells holds promise as a treatment, but effectively delivering gene-targeting drugs to the brain remains elusive, according to the university in a March 16, 2025 press release.

“Given their ability to modulate genetic expression in cells, ASOs have become a hot topic in medical research. These compounds consist of a piece of single-stranded DNA with a base sequence that is complementary to a target messenger RNA (mRNA). By binding to their target, ASOs can prevent the production of specific proteins in cells. Despite their potential, ASOs fail to reach the brain effectively and tend to be quickly cleared from the bloodstream,” the university stated in its release (1).

Therefore, to address this issue, the university’s research team focused on a new type of gene-targeting compound, heteroduplex oligonucleotides (HDOs). HDOs operate similarly to ASOs except that they carry an additional complementary RNA strand that enhances their stability and specificity. This extra RNA strand can be further modified by attaching a cholesterol (Chol) molecule to create Chol-HDOs compounds. Because recent reports discussed the enhanced ability of Chol-HDO to reach various organs in the body—including the brain—Nishikawa’s team sought to clarify the pharmacokinetics of these compounds in comparison to ASOs and HDOs. Their aim is to shed light on how Chol-HDOs are distributed within the body. According to their findings, the key to success lies in how Chol-HDOs interact with proteins in the blood.

“We found that, while HDOs bind electrostatically to serum proteins with low binding affinity and are taken up by cells, Chol-HDOs bind tightly to serum proteins, including lipoproteins, via hydrophobic interactions,” said Nishikawa in a March 16, 2025 press release (1). “This strong binding of Chol-HDOs to serum proteins results in slow clearance from the bloodstream.”

“The possibility of efficiently delivering ASOs and other nucleic acid-based drugs to the brain may lead to the development of treatments for brain diseases with significant unmet medical needs,” Nishikawa added in the release.

The university estimates that more than 55 million people are living with dementia today, which is caused by diseases that could be treatable, or at least preventable, if the right compounds could be delivered beyond the blood-brain barrier. Meanwhile, approximately 300,000 cases of brain cancers are reported worldwide annually, the university estimates. Continued research on modified HDOs could potentially pave the way for a new generation of drugs that effectively target brain diseases (1).

References

1. Tokyo University of Science. Towards Gene-Targeting Drugs Capable of Targeting Brain Diseases. Press Release. March 16, 2025.
2. United Nations. The 17 Goals. sdgs.un.org/goals (accessed April 17, 2025).
3. Yoshioka, Y.; Yamamoto, S.; Kusamori, K.; et al. Pharmacokinetics and Protein Binding of Cholesterol-Conjugated Heteroduplex Oligonucleotide. J. Controlled Release 2025, 380, 787–799. DOI: 10.1016/j.jconrel.2025.02.025