Lysosomal storage diseases and the blood-brain barrier.
The blood-brain barrier becomes a crucial issue in neuronopathic lysosomal storage diseases for three reasons. Firstly, the function of the blood-brain barrier may be compromised in many of the lysosomal storage diseases and this barrier dysfunction may contribute to the neuropathology seen in the diseases and accelerate cell death. Secondly, the substrate reduction therapies, which successfully reduce peripheral lysosomal storage, because of the blood-brain barrier may not have as free an access to brain cells as they do to peripheral cells. And thirdly, enzyme replacement therapy appears to have little access to the central nervous system as the mannose and mannose-6-phosphate receptors involved in their cellular uptake and transport to the lysosome do not appear to be expressed at the adult blood-brain barrier. This review will discuss in detail these issues and their context in the development of new therapeutic strategies.
Begley
David J
DJ
Kings College London, Blood-Brain Barrier Group, Pharmaceutical Sciences Division, Hodgkin Building, Guys Campus London, SE1 1UL, UK. david.begley@kcl.ac.uk
Pontikis
Charles C
CC
Scarpa
Maurizio
M
D000818:Animals; D000831:Animals, Newborn; D001812:Blood-Brain Barrier / Q000254:growth & development / Q000378:metabolism* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D006867:Hydrolases / Q000493:pharmacokinetics / Q000627:therapeutic use; D016464:Lysosomal Storage Diseases / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008358:Mannose / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D017527:Receptor, IGF Type 2; D011994:Recombinant Proteins; D006867:Hydrolases; D008358:Mannose