New! Sign up for our free email newsletter.
Science News
from research organizations

Sweet move: a modified sugar enhances antisense oligonucleotide safety and efficacy

May 22, 2024
Tokyo Medical and Dental University
Researchers found that adding a newly developed modified sugar, BNAP-AEO, to gapmer antisense oligonucleotides (ASOs) increased their affinity for target RNAs, thus significantly enhancing their gene-silencing effects in vitro and in vivo. The BNAP-AEO modification also decreased gapmer ASO toxicity to the central nervous system (CNS), suggesting that it could improve the clinical application of ASO treatment of CNS disease.

Diseases that affect the brain and spinal cord can be particularly devastating, and finding new and more effective ways to treat these conditions is an important goal for researchers and clinicians alike. Now, a research group from Japan reports that slightly modifying an existing treatment for central nervous system (CNS) disease dramatically increases its effectiveness.

In a study published recently in Molecular Therapy Nucleic Acids, researchers from Tokyo Medical and Dental University (TMDU) and Osaka University have revealed that adding a modified sugar to antisense oligonucleotides (ASOs), a recently developed treatment strategy for CNS disease caused by toxic proteins, greatly decreases disease symptoms.

Multiple ASOs have been approved for clinical use, including gapmer ASOs, which are small pieces of genetic material binding to RNA messenger molecules that produce mutant disease-causing proteins to flag them for degradation. Modifying the chemical composition of these gapmer ASOs can both increase their ability to target molecules for degradation and decrease the toxic side effects of the treatment.

"We recently developed a new chemical modification called BNAP-AEO," says lead author of the study Taiki Matsubayashi. "While ASOs carrying BNAP-AEO are expected to be highly effective, their biological efficacy and toxicity have not been investigated."

To characterize gapmer ASOs modified by the inclusion of BNAP-AEO, the researchers first evaluated the stability of gapmer ASO binding to target molecules at different temperatures. They then tested the ability of these modified gapmer ASOs to block the production of disease-causing proteins in brain cancer cells and in mice.

"The results were very exciting," explains Takanori Yokota, senior author. "Not only did ASOs carrying BNAP-AEO have a higher binding affinity for the target than those without BNAP-AEO, they also induced more efficient gene silencing in vitro and strongly suppressed gene expression in the mouse brain."

Furthermore, modifying gapmer ASOs with BNAP-AEO decreased their toxic side effects in mice, possibly by changing their interactions with receptors on the surface of cells in the brain and spinal cord.

"Our findings highlight the efficient gene-silencing effect of ASOs incorporating BNAP-AEO, as well as an unexpected role for this modification in decreasing CNS toxicity," says Matsubayashi.

In addition to providing a new way to increase the efficacy and safety of gapmer ASOs, the results from this study suggest that ASOs that bind stably at high temperatures are not necessarily more potent, as is commonly thought. This could be explained by the BNAP-AEO chemical modification affecting other features of the ASOs, such as which cell compartment they localize to.

Story Source:

Materials provided by Tokyo Medical and Dental University. Note: Content may be edited for style and length.

Journal Reference:

  1. Taiki Matsubayashi, Kotaro Yoshioka, Su Su Lei Mon, Maho Katsuyama, Chunyan Jia, Takao Yamaguchi, Rintaro Iwata Hara, Tetsuya Nagata, Osamu Nakagawa, Satoshi Obika, Takanori Yokota. Favorable efficacy and reduced acute neurotoxicity by antisense oligonucleotides with 2′,4′-BNA/LNA with 9-(aminoethoxy)phenoxazine. Molecular Therapy - Nucleic Acids, 2024; 102161 DOI: 10.1016/j.omtn.2024.102161

Cite This Page:

Tokyo Medical and Dental University. "Sweet move: a modified sugar enhances antisense oligonucleotide safety and efficacy." ScienceDaily. ScienceDaily, 22 May 2024. <>.
Tokyo Medical and Dental University. (2024, May 22). Sweet move: a modified sugar enhances antisense oligonucleotide safety and efficacy. ScienceDaily. Retrieved June 19, 2024 from
Tokyo Medical and Dental University. "Sweet move: a modified sugar enhances antisense oligonucleotide safety and efficacy." ScienceDaily. (accessed June 19, 2024).

Explore More

from ScienceDaily