Targeting of the CNS in MPS-IH using a nonviral transferrin-alpha-L-iduronidase fusion gene product.
Mucopolysaccharidosis type I (Hurler syndrome) is caused by a deficiency of the enzyme alpha-L-iduronidase (IDUA), and is characterized by widespread lysosomal glycosaminoglycan (GAG) accumulation. Successful treatment of central nervous system (CNS) diseases is limited by the presence of the blood-brain barrier, which prevents penetration of the therapeutic enzyme. Given that the brain capillary endothelial cells that form this barrier express high levels of the transferrin receptor (TfR), we hypothesized that the coupling of IDUA to transferrin (Tf) would facilitate IDUA delivery to the CNS. A plasmid bearing a fusion gene consisting of Tf and IDUA was constructed which, when delivered in vivo, resulted in the production of high levels of an enzymatically active protein that was transported into the CNS by TfR-mediated endocytosis. Short-term treatment resulted in a decrease in GAGs in the cerebellum of mucopolysaccharidosis type I (MPS I) mice. This approach, therefore, represents a potential strategy for the delivery of therapeutic enzyme to the CNS.
Osborn
Mark J
MJ
University of Minnesota Cancer Center, Minneapolis, Minnesota, USA.
McElmurry
Ron T
RT
Peacock
Brandon
B
Tolar
Jakub
J
Blazar
Bruce R
BR
D000818:Animals; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D002196:Capillaries / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D003587:Cytomegalovirus / Q000235:genetics; D016503:Drug Delivery Systems / Q000379:methods; D005455:Fluorescent Antibody Technique; D015316:Genetic Therapy / Q000379:methods; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D007068:Iduronidase / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D009083:Mucopolysaccharidoses / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D041681:NIH 3T3 Cells; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014168:Transferrin / Q000235:genetics* / Q000378:metabolism
D006025:Glycosaminoglycans; D011990:Receptors, Transferrin; D011993:Recombinant Fusion Proteins; D014168:Transferrin; D007068:Iduronidase