This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Nucleic acid therapeutics, such as antisense oligonucleotides (ASOs), have emerged as promising platforms for treating a variety of previously hard-to-treat diseases, including neurological diseases. Over the past decade, ASO drugs have been approved worldwide for hereditary amyotrophic lateral sclerosis and spinal muscular atrophy.
These drugs are administered directly into the cerebrospinal fluid (CSF) via lumbar puncture, a method known as intrathecal administration, enabling them to reach the brain and spinal cord. ASOs are short, synthetic, single-stranded strings of nucleic acids (deoxyribonucleic acid or ribonucleic acid (RNA)) designed to bind to a specific RNA in the body. By binding to RNA, ASOs can stop, reduce or modify the production of disease-causing proteins.
Despite their precision, current ASO therapies face challenges related to both effectiveness and safety. To function as drugs, ASOs require chemical modifications that improve their stability and cellular uptake. One widely used design features a phosphorothioate (PS) backbone combined with a 2′-O-methoxyethyl (MOE) modification, which enhances potency.
However, PS-MOE ASOs can cause neurotoxic effects, including sedation following intrathecal administration. In contrast, phosphorodiamidate morpholino oligomer (PMO) ASOs are safer, even at high dosages, but have lower potency, requiring frequent administration and increasing patient burden. To address these issues, a research team led by Dr.
Takanori Yokota at the Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo (Science Tokyo), Japan, has developed a nucleic acid platform that achieves both high efficacy and safety. The same research group had previously developed PMO-based heteroduplex oligonucleotides (HDOs) and demonstrated their efficacy throughout the body, including in skeletal and cardiac muscles, as well as in the central nervous system by crossing the blood-brain barrier, in a mouse model of Duchenne muscular dystrophy. Building on this foundation, the present study applied the PMO-based HDO technology to the central nervous system and further advanced the technology through intrathecal administration.
"In this study, we designed an improved nucleic acid platform, combining heteroduplex oligonucleotide (HDO) with PMO and its complementary RNA, and further conjugating it with cholesterol, creating Chol-HDO[PMO]," explains Yanagidaira. Their findings were published in the journal Nature Communications on Dec. 22, 2025. The researchers tested the splicing and translation-blocking abilities of cholesterol-conjugated PMO/RNA HDO (Chol-HDO[PMO]) in mouse models by administering it into the CSF.
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