New chemical modification improves efficacy and safety of ASO therapy for CNS diseases

Diseases affecting 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 team from Japan reports that slightly modifying an existing treatment for central nervous system (CNS) disease dramatically increases its effectiveness.

In a study recently published in Molecular therapy Nucleic AcidsResearchers 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, significantly reduces symptoms of the disease.

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

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

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

The results were very exciting. Not only did ASOs bearing BNAP-AEO have higher binding affinity for the target than those without BNAP-AEO, but they also induced more efficient gene silencing in vitro and strongly suppressed gene expression in the mouse brain.”

Takanori Yokota, senior author

Furthermore, modification of gamer ASOs with BNAP-AEO reduced their toxic side effects in mice, possibly by altering their interactions with cell surface receptors in the brain and spinal cord.

“Our findings highlight the effective gene silencing effect of ASOs incorporating BNAP-AEO, as well as an unexpected role of this modification in reducing CNS toxicity,” says Matsubayashi.

In addition to providing a new way to increase the efficacy and safety of gamer ASOs, the results of this study suggest that ASOs that bind stably at elevated temperatures are not necessarily more potent, as commonly believed. This could be explained by the chemical modification of BNAP-AEO affecting other characteristics of ASOs, such as in which cellular compartment they localize.