Targeted enzyme delivery systems for treatment of orphan niemann-pick disease

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DESCRIPTION (provided by applicant): Type A and B Niemann-Pick disease (NPD) is a chronic lysosomal storage disorder (LSD) due to a genetic deficiency of acid sphingomyelinase (ASM), which causes aberrant accumulation of sphingomyelin and cholesterol. Storage in the reticulo-endothelial system (RES; sphingomyelin scavengers) and vascular endothelial cells (ECs; a major ASM source) causes hepatosplenomegaly, vascular dystonia, thrombosis, atherosclerosis, and pulmonary inflammation. As a consequence, NPD results in high morbidity and premature mortality in patients. Enzyme replacement therapy (ERT) for NPD depends on receptors that recognize ASM sugar residues and induce clathrin-mediated uptake. Suboptimal glycosylation of recombinant ASM and altered clathrin-dependent endocytosis in NPD cells limit enzyme delivery. This justifies the design of alternative strategies, yet development of novel NPD therapies is hampered due to low incidence of this orphan disease. We hypothesize that effective ERT requires means bypassing glycosylation and clathrin pathways and propose an alternative strategy: targeting Intercellular Adhesion Molecule (ICAM) -1, a glycoprotein expressed on diverse cell types (predominantly ECs and RES), up-regulated and functionally involved in NPD pathology. We showed that prototype ICAM-1-targeted nanocarriers (polystyrene beads coated with anti-ICAM and ASM) are internalized by cells via CAM-mediated endocytosis (a non-classical pathway that is not affected in NPD) and enhance ASM targeting in mice and lysosomal delivery in cells. Evaluation of the therapeutic utility of this strategy will require recurrent administrations, compelling substitution of immunogenic antibody and non-degradable beads by viable compounds. We propose to explore ASM delivery by biocompatible PLGA nanocarriers targeted by anti-ICAM single-chain Fv (scFv). We hypothesize that this system will: a) deliver ASM to NPD organs and cells; b) address ASM to lysosomes; and c) restore ASM activity. We will test these hypotheses in the following Aims: 1-Characterize targeting of ICAM-1-addressed ASM; 2-Define lysosomal delivery of ICAM-1-targeted ASM; and 3-Evaluate the recovery of ASM activity delivered by ICAM-1-targeted system, in both cells and animal models. This study will provide a biocompatible system suitable for future studies on the safety and therapeutic utility of ICAM-1-targeted NPD ERT. The clinical benefits of this strategy may be extended to other LSDs.