Intrathecal Delivery of Antisense Oligonucleotide Therapeutics

Download or read book Intrathecal Delivery of Antisense Oligonucleotide Therapeutics written by Brynna Wilken-Resman and published by . This book was released on 2019 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Antisense oligonucleotide (ASO) therapies for central nervous system (CNS) indications have advanced significantly within the past three years, including FDA approval for an ASO therapy for spinal muscular atrophy and clinical trials for several other neurological disorders. ASOs are ~6-8 kDa, single-stranded DNA or RNA oligomers and are attractive therapeutic candidates for diseases caused by known genetic abnormalities because they are disease-modifying therapeutics that can interact with target RNA to modify protein production. ASOs are unable to cross the blood-brain barrier on their own, so they are administered centrally, typically achieved by intrathecal administration. Despite the clinical use of CSF-administered ASOs, there is a paucity of knowledge concerning CSF-to-brain transport mechanisms and the resulting CNS biodistribution. Here, we investigated ASO transport and distribution in the CNS following intrathecal administration, focusing on the effects of different ASO chemistries and two transport mechanisms: diffusion in the extracellular spaces and convection/dispersion in perivascular spaces (PVS) surrounding the cerebral vasculature. We have demonstrated that intrathecal administration of fluorescently-labeled ASOs in rats leads to limited diffusion at CSF-brain and CSF-spinal cord interfaces and rapid distribution within the PVS. ASOs distributed to the PVS surrounding vessels of all type and caliber. We have also demonstrated that the extent to which perivascular distribution occurs differs in a sequence- and chemical modification-specific manner, a finding not yet reported in the literature. Furthermore, we have found that ASOs with a nucleotide sequence that allowed a random coil conformation had a significantly smaller hydrodynamic size compared to ASOs that formed secondary structures and that smaller hydrodynamic size correlated with more extensive diffusion and perivascular access. The difference in perivascular signal between the PS-ASO and the 2'MOE-ASO was significant when quantified and was particularly apparent in the dorsal cortex as well as in subcortical brain regions such as the striatum and hippocampus. Biodistribution and transport studies such as those conducted in the present work may provide an improved framework for understanding ASO delivery to brain and spinal cord targets. It is our hope that this framework may assist in developing ASO therapies for optimal CNS distribution to improve treatment results for devastating neurological conditions.