Antisense oligonucleotide therapies get delivered across the blood-brain barrier

Researchers have demonstrated that heteroduplex oligonucleotide drugs conjugated with cholesterol efficiently cross the blood-brain barrier and can be used to treat central nervous system (CNS) diseases. 

Antisense oligonucleotide (ASO) therapeutics are molecules that contain 18 to 30 base pairs that modify expression of a target mRNA, with the goal of suppressing harmful proteins or noncoding RNAs. These base pairs are ordered in reverse (antisense) and prevent the production of pathogenic proteins through binding to the “sense” strand of mRNA targets. In general, only small hydrophobic molecules with a molecular weight of less than 450 dalton can penetrate the blood-brain barrier and the blood-cerebrospinal fluid barrier. ASOs are highly polar and thus generally do not enter the brain intact after system administration. Researchers from Tokyo Medical and Dental University, Takeda Pharmaceutical, and Ionis Pharmaceuticals have developed DNA/RNA heteroduplex oligonucleotides (HDOs) conjugated to cholesterol (Chol-HDO) or alpha-tocopherol (Toc-HDO) as a drug delivery platform. They hope the technology will overcome the limited efficacy of ASOs targeting the CNS without requiring intrathecal administration.

The results appeared in August 12th online issue of Nat Biotechnol (

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