title: Intracisternal enzyme replacement therapy in lysosomal storage diseases: routes of absorption into brain.
abstract: OBJECTIVE
  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.
authors.affiliation: Institute of Veterinary, Animal and Biomedical Sciences, Massey University, Palmerston North, New Zealand. r.d.jolly@massey.ac.nz
authors.forename: R D
authors.initials: RD
authors.lastname: Jolly
authors.forename: N R
authors.initials: NR
authors.lastname: Marshall
authors.forename: M R
authors.initials: MR
authors.lastname: Perrott
authors.forename: K E
authors.initials: KE
authors.lastname: Dittmer
authors.forename: K M
authors.initials: KM
authors.lastname: Hemsley
authors.forename: H
authors.initials: H
authors.lastname: Beard
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002946:Cisterna Magna / Q000187:drug effects; D004285:Dogs; D056947:Enzyme Replacement Therapy / Q000379:methods*; D006801:Humans; D006867:Hydrolases / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D009084:Mucopolysaccharidosis III / Q000628:therapy*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D013116:Spinal Cord / Q000187:drug effects
chemical_list: D011994:Recombinant Proteins; D006867:Hydrolases; C022708:N-sulfoglucosamine sulfohydrolase