Antisense oligonucleotides (AONs) are versatile molecules that can be used to modulate gene expression by binding to RNA. The therapeutic potential of AONs appears particularly high in the central nervous system, due to excellent distribution and uptake in brain cells, as well as good tolerability in clinical trials thus far. Nonetheless, immune stimulation in response to AON treatment in the brain remains a concern. For this reason we performed RNA sequencing analysis of brain tissue from mice treated intracerebroventricularly with phosphorothioate, 2′-O-methyl modified AONs. A significant upregulation of immune system associated genes was observed in brains of AON treated mice, with the striatum showing largest transcriptional changes. Strongest upregulation was seen for the antiviral enzyme 2′-5′-oligoadenylate synthase-like protein 2 (Oasl2) and Bone marrow stromal antigen 2 (Bst2). Histological analysis confirmed activation of microglia and astrocytes in striatum. The upregulation of immune system associated genes was detectable for at least 2 months after the last AON administration, consistent with a continuous immune response to the AON.
Drug delivery to the central nervous system (CNS) is complicated by the blood-brain barrier. As a result, many agents that are found to be potentially effective at their site of action cannot be sufficiently or effectively delivered to the CNS and therefore have been discarded and not developed further for clinical use, leaving many CNS diseases untreated. One way to overcome this obstacle is intracerebroventricular (ICV) delivery of the therapeutics directly to cerebrospinal fluid (CSF). Recent experimental and clinical findings reveal that CSF flows from the ventricles throughout the parenchyma towards the subarachnoid space also named minor CSF pathway, while earlier, it was suggested that only in pathological conditions such as hydrocephalus this form of CSF flow occurs. This transependymal flow of CSF provides a route to distribute ICV-infused drugs throughout the brain. More insight on transependymal CSF flow will direct more rational to ICV drug delivery and broaden its clinical indications in managing CNS diseases.
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