Abstract
Large blood vessels entering the CNS are surrounded by perivascular spaces that communicate with the cerebrospinal fluid and, at their termini, with the interstitial space. Solutes and particles can translocate along these perivascular conduits, reportedly in both directions. Recently, this prompted a renewed interest in the intrathecal therapy delivery route for CNS-targeted therapeutics. However, the extent of the CNS coverage by the perivascular system is unknown, making the outcome of drug administration to the CSF uncertain. We traced the translocation of model macromolecules from the CSF into the CNS of rats and non-human primates. Conduits transporting macromolecules were found to extend throughout the parenchyma from both external and internal (fissures) CNS boundaries, excluding ventricles, in large numbers, on average ca. 40 channels per mm2 in rats and non-human primates. The high density and depth of extension of the perivascular channels suggest that the perivascular route can be suitable for delivery of therapeutics to parenchymal targets throughout the CNS.
Highlights
The major problem in developing therapies for diseases involving the CNS is the lack of safe and efficient means to overcome the blood–brain, blood-cerebrospinal fluid and blood-arachnoid barriers (Misra et al, 2003)
Accumulating evidence suggests that highly potent biopharmaceuticals can exert measurable biological effects in the CNS after administration to the cerebrospinal fluid (CSF) (Meuli-Simmen et al, 1999; Shi et al, 2003; Kakkis et al, 2004; Milligan et al, 2006; Ishigaki et al, 2007; Tsai et al, 2007; Hemsley and Hopwood, 2009), which renewed the interest in the intrathecal (IT) drug delivery route
RhNAGLU was sufficiently stable after internalization by cells to study its deposition in the CNS cells 24 h post administration (Supplementary Figure S1), i.e., at the time when the free protein has been already cleared from the CSF (Supplementary Figure S2)
Summary
The major problem in developing therapies for diseases involving the CNS is the lack of safe and efficient means to overcome the blood–brain, blood-cerebrospinal fluid and blood-arachnoid barriers (Misra et al, 2003). The exclusion of macromolecules from the CNS is trying because biopharmaceuticals, all of which are large molecules or supramolecular constructs [proteins (Barinaga, 1994; Cheng and Smith, 2003; Zhang and Pardridge, 2005), oligonucleotides (Banks et al, 2001; Vinogradov et al, 2004), gene vectors (Kaplitt et al, 1994; Fink et al, 1996; Pardridge, 2002)], could be potent as therapies for many diseases involving the CNS (Banks, 2008; Becker et al, 2008; Mitragotri et al, 2014). The only plausible explanation of macromolecule entry into the CNS appears to be through the perivascular spaces (conduits)
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