Intracisternal enzyme replacement therapy in lysosomal storage diseases: routes of absorption into brain

R. D. Jolly, N. R. Marshall, M. R. Perrott, K. E. Dittmer, K. M. Hemsley and H. Beard (2011) Neuropathology and Applied Neurobiology37, 414–422 Intracisternal enzyme replacement therapy in lysosomal storage diseases: routes of absorption into brain Aims: The research concerns enzyme replacement therapy in lysosomal storage diseases with central nervous system involvement. The principle aim was to understand the routes of entry of enzyme into the brain when delivered directly into the cerebrospinal fluid (CSF) via the cerebellomedullary cistern. Methods: Pathways for absorption of replacement enzyme were investigated in dogs with mucopolysaccharidosis IIIA (MPSIIIA) following intracisternal injections of human recombinant N-sulphoglucosamine sulphohydrolase (rhSGSH, EC3.10.1.1) by light and confocal microscopy using chromogenic and fluorescent immune probes. Results: Enzyme entered the brain superficially by penetration of the pia/glia limitans interface, but the main route was perivascular along large veins, arteries and arterioles extending onto capillaries. It further dispersed into surrounding neuropil to be taken up by neurones, macrophages, astrocytes and oligodendroglia. Enzyme also entered the lateral ventricles adjacent to the choroid plexus, probably also by the tela choroidea and medullary velum, with further spread throughout the ventricular system and spinal canal. There was secondary spread back across the ependyma into nervous tissue of brain and spinal cord. Conclusions: Enzyme mainly enters the brain by a perivascular route involving both arteries and veins with subsequent spread within the neuropil from where it is taken up by a proportion of neurones and other cells. Penetration of enzyme through the pia/glia limitans is minor and superficial.