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: Silvia Muro, Edward H Schuchman, Vladimir R Muzykantov
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 13 Issue 1 Pg. 135-41 (Jan 2006) ISSN: 1525-0016 [Print] United States
• PMID: 16153895 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Clathrin
• Recombinant Proteins
• Intercellular Adhesion Molecule-1
• Sphingomyelin Phosphodiesterase

Topics

• Antibodies, Monoclonal (chemistry)
• Cells, Cultured
• Clathrin (physiology)
• Drug Delivery Systems
• Endocytosis
• Endothelial Cells (enzymology)
• Fibroblasts (enzymology)
• Glycosylation
• Humans
• Intercellular Adhesion Molecule-1 (immunology, metabolism)
• Lysosomes (enzymology)
• Nanostructures
• Niemann-Pick Diseases (enzymology)
• Recombinant Proteins (administration & dosage, metabolism)
• Sphingomyelin Phosphodiesterase (administration & dosage, metabolism)