title: Lysosomal enzyme delivery by ICAM-1-targeted nanocarriers bypassing glycosylation- and clathrin-dependent endocytosis.
abstract: Enzyme replacement therapy, a state-of-the-art treatment for many lysosomal storage disorders, relies on carbohydrate-mediated binding of recombinant enzymes to receptors that mediate lysosomal delivery via clathrin-dependent endocytosis. Suboptimal glycosylation of recombinant enzymes and deficiency of clathrin-mediated endocytosis in some lysosomal enzyme-deficient cells limit delivery and efficacy of enzyme replacement therapy for lysosomal disorders. We explored a novel delivery strategy utilizing nanocarriers targeted to a glycosylation- and clathrin-independent receptor, intercellular adhesion molecule (ICAM)-1, a glycoprotein expressed on diverse cell types, up-regulated and functionally involved in inflammation, a hallmark of many lysosomal disorders. We targeted recombinant human acid sphingomyelinase (ASM), deficient in types A and B Niemann-Pick disease, to ICAM-1 by loading this enzyme to nanocarriers coated with anti-ICAM. Anti-ICAM/ASM nanocarriers, but not control ASM or ASM nanocarriers, bound to ICAM-1-positive cells (activated endothelial cells and Niemann-Pick disease patient fibroblasts) via ICAM-1, in a glycosylation-independent manner. Anti-ICAM/ASM nanocarriers entered cells via CAM-mediated endocytosis, bypassing the clathrin-dependent pathway, and trafficked to lysosomes, where delivered ASM displayed stable activity and alleviated lysosomal lipid accumulation. Therefore, lysosomal enzyme targeting using nanocarriers targeted to ICAM-1 bypasses defunct pathways and may improve the efficacy of enzyme replacement therapy for lysosomal disorders, such as Niemann-Pick disease.
authors.affiliation: Institute for Environmental Medicine, University of Pennsylvania Medical School, 1 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104-6068, USA. silvia@mail.med.upenn.edu
authors.forename: Silvia
authors.initials: S
authors.lastname: Muro
authors.forename: Edward H
authors.initials: EH
authors.lastname: Schuchman
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Muzykantov
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry; D002478:Cells, Cultured; D002966:Clathrin / Q000502:physiology*; D016503:Drug Delivery Systems; D004705:Endocytosis; D042783:Endothelial Cells / Q000201:enzymology; D005347:Fibroblasts / Q000201:enzymology; D006031:Glycosylation; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism*; D008247:Lysosomes / Q000201:enzymology*; D049329:Nanostructures; D009542:Niemann-Pick Diseases / Q000201:enzymology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D002966:Clathrin; D011994:Recombinant Proteins; D018799:Intercellular Adhesion Molecule-1; D013108:Sphingomyelin Phosphodiesterase