A study using mouse and rat models showed that DNA/RNA heteroduplex oligonucleotides (HDOs) conjugated to cholesterol or α-tocopherol can reach the central nervous system (CNS) after subcutaneous or intravenous administration. This finding suggests that cholesterol-conjugated HDOs may overcome the limited efficacy of antisense oligonucleotides that target the CNS through intrathecal injection, which is more invasive than intravenous injection.

The efficacy of single-stranded antisense oligonucleotides has been extensively studied for the treatment of CNS disorders such as spinal muscular atrophy (SMA). In fact, nusinersen (Spinraza®), a single-stranded antisense oligonucleotide that modulates the splicing of SMN2 mRNA to treat the disease, has recently been approved by the US Food and Drug Administration (FDA). However, nusinersen must be administered into the spinal canal to reach the CNS. 

Being able to modulate gene expression in the CNS by delivering antisense oligonucleotides directly into the bloodstream would be advantageous and less invasive.

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In a study recently published in Nature Biotechnology, a team of researchers led by Takanori Yokota, MD, PhD, showed that HDOs distributed throughout the brain, spinal cord, and peripheral tissues after subcutaneous or intravenous injection and suppressed the expression of 4 target genes by up to 90% in the CNS. These were the metastasis-associated lung adenocarcinoma transcript 1 (malat1) gene, an RNA gene associated with hyperglycemia and acute monocytic leukemia; the DMPK gene associated with myotonic dystrophy type 1; the Gfap gene, mutations in which cause Alexander disease; and the SOD1 gene associated with amyotrophic lateral sclerosis (ALS). 

The researchers wrote, “Gene knockdown was observed in major CNS cell types and was greatest in neurons and microglial cells.” Side effects, such as thrombocytopenia and focal brain necrosis, could be limited by using subcutaneous delivery or by dividing intravenous injections.

“By crossing the blood-brain barrier more effectively, cholesterol-conjugated HDOs may overcome the limited efficacy of [antisense oligonucleotides] targeting the CNS without requiring intrathecal administration,” the researchers concluded. 


Nagata T, Dwyer CA, Yoshida-Tanaka K, et al. Cholesterol-functionalized DNA/RNA heteroduplexes cross the blood-brain barrier and knock down genes in the rodent CNS. Nat Biotechnol. Published online August 12, 2021. doi:10.1038/s41587-021-00972-x