Targeting Intercellular Adhesion Molecule-1 to Enhance Delivery of Therapeutic Enzymes for Treatment of Lysosomal Storage Diseases

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Hsu, Janet
Muro, Silvia
Lysosomal storage diseases (LSDs) are a group of more than 40 genetically inherited diseases that result from dysfunction of specific proteins, often an enzyme, located in lysosomes within cells which leads to abnormal lysosomal accumulation of specific macromolecules. As a result, cell malfunction occurs and escalates into multi-tissue and multi-organ failures, often resulting in premature death. For several early onset LSDs, the central nervous system (CNS) is also affected and manifests fatal neuropathic and/or neurodegenerative symptoms. Within the last two decades, treatment for selective LSDs has become clinically available. Specifically, enzyme replacement therapy (ERT) by intravenous injection of recombinant enzymes holds relevant promise. Yet current ERT results in suboptimal enzyme biodistribution to many target organs, including the peripheral organs and also the CNS. Delivery to the CNS is particularly impeded due to the tight blood-brain barrier (BBB) that strictly regulates passage between the circulation system and the brain tissue. We explored the use of targeted drug delivery systems to address this issue. Specifically, we focused on targeting intercellular adhesion molecule-1 (ICAM-1), a cell surface glycoprotein that is upregulated under pathological conditions, including LSDs. In this dissertation, using in vitro, cell culture, and in vivo techniques, we examined whether ICAM-1-targeted polymer nanocarriers: (1) enhance binding, uptake, and lysosomal delivery of different enzymes in cells, (2) provide targeting and transport across endothelial and subendthelial cells of the BBB, and (3) improve accumulation of lysosomal enzymes to peripheral organs and the brain. Results suggest that after intravenous injection of enzyme coupled to ICAM-1-targeted nanocarriers, ICAM-1 targeting shift these enzymes from the circulation to tissues, enhancing enzyme accumulation over non-targeted counterparts both in peripheral organs and the brain. This could be modulated by varying parameters such as the density of targeting antibodies on the carrier coat or the carrier bulk concentration. Also, ICAM-1-targeted nanocarriers were transported across BBB models followed by uptake and lysosomal transport to neuron-like cells. ICAM-1-targeted nanocarriers preferentially bound to diseased cells and were internalized and trafficked to lysosomes, resulting in degradation of the accumulated substrate. Therefore, overall, ICAM-1-targeting shows promise in improving ERT for LSD treatment.