1. ¹Institute for Environmental Medicine, University of Pennsylvania Medical School, 1 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104-6068, USA
2. ²Department of Pharmacology, University of Pennsylvania Medical School, 1 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104-6068, USA
3. ³Department of Human Genetics, Mount Sinai School of Medicine, Room 14-20A, 1425 Madison Avenue, New York, NY 10029, USA

Correspondence: Silvia Muro, Fax: +1 215 898 0868. E-mail: silvia@mail.med.upenn.edu

Received 12 April 2005; Revised 19 July 2005; Accepted 19 July 2005.

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.