Imaging of enzyme replacement therapy using PET

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-06, Vol.107 (24), p.10842-10847
• Main Authors: Phenix, Christopher P, Rempel, Brian P, Colobong, Karen, Doudet, Doris J, Adam, Michael J, Clarke, Lorne A, Withers, Stephen G
• Format: Article
• Language: English
• Subjects: Active sites; Amino Acid Substitution; Animals; beta-Glucosidase - genetics; beta-Glucosidase - metabolism; Biochemistry; Biological Sciences; Catalytic Domain; Cells; Clinical medicine; Enzyme replacement therapy; Enzymes; Enzymes - pharmacokinetics; Enzymes - therapeutic use; Fluorides; Fluorine Radioisotopes; Gaucher disease; Gaucher Disease - diagnostic imaging; Gaucher Disease - drug therapy; Gaucher Disease - enzymology; Genetics; Glucosylceramidase - pharmacokinetics; Glucosylceramidase - therapeutic use; Half-Life; Humans; Imaging; Lectins, C-Type - antagonists & inhibitors; Lectins, C-Type - metabolism; Liver; Mannose-Binding Lectins - antagonists & inhibitors; Mannose-Binding Lectins - metabolism; Mice; Mice, Inbred C57BL; Mutagenesis, Site-Directed; Positron emission tomography; Positron-Emission Tomography - methods; Radiopharmaceuticals; Receptors; Receptors, Cell Surface - antagonists & inhibitors; Receptors, Cell Surface - metabolism; Recombinant Proteins - genetics; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - therapeutic use; Rhizobium - enzymology; Rhizobium - genetics; Tissue Distribution
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1003247107

Direct enzyme replacement therapy (ERT) has been introduced as a means to treat a number of rare, complex genetic conditions associated with lysosomal dysfunction. Gaucher disease was the first for which this therapy was applied and remains the prototypical example. Although ERT using recombinant lysosomal enzymes has been shown to be effective in altering the clinical course of Gaucher disease, Fabry disease, Hurler syndrome, Hunter syndrome, Maroteaux-Lamy syndrome, and Pompe disease, the recalcitrance of certain disease manifestations underscores important unanswered questions related to dosing regimes, tissue half-life of the recombinant enzyme and the ability of intravenously administered enzyme to reach critical sites of known disease pathology. We have developed an innovative method for tagging acid β-glucocerebrosidase (GCase), the recombinant enzyme formulated in Cerezyme® used to treat Gaucher disease, using an ¹⁸F-labeled substrate analogue that becomes trapped within the active site of the enzyme. Using micro-PET we show that the tissue distribution of injected enzyme can be imaged in a murine model and that the PET data correlate with tissue ¹⁸F counts. Further we show that PET imaging readily monitors pharmacokinetic changes effected by receptor blocking. The ability to ¹⁸F-label GCase to monitor the enzyme distribution and tissue half-life in vivo by PET provides a powerful research tool with an immediate clinical application to Gaucher disease and a clear path for application to other ERTs.