Targeting macrophages with baculovirus‐produced lysosomal enzymes: implications for enzyme replacement therapy of the glycoprotein storage disorder galactosialidosis

• Published in: The FASEB journal 2004-06, Vol.18 (9), p.971-973
• Main Authors: Bonten, Erik J., Wang, Dongning, Toy, James N., Mann, Linda, Mignardot, Aurélie, Yogalingam, Gouri, d'Azzo, Alessandra
• Format: Article
• Language: English
• Subjects: Animals; Baculoviridae - genetics; beta-Glucosidase - administration & dosage; beta-Glucosidase - biosynthesis; beta-Glucosidase - genetics; beta-Glucosidase - therapeutic use; Catalysis; Cathepsin A - administration & dosage; Cathepsin A - genetics; Cathepsin A - metabolism; Cathepsin A - therapeutic use; Cell Line; Gene Deletion; Humans; Kidney - drug effects; Kidney - pathology; Liver - chemistry; Liver - drug effects; Liver - metabolism; Liver - pathology; lysosomal storage diseases; Lysosomal Storage Diseases - drug therapy; Lysosomal Storage Diseases - enzymology; Lysosomal Storage Diseases - pathology; Lysosomes - enzymology; Macrophages - cytology; Macrophages - drug effects; Macrophages - enzymology; Mice; Neuraminidase - administration & dosage; Neuraminidase - genetics; Neuraminidase - metabolism; Neuraminidase - therapeutic use; Oligosaccharides - chemistry; Oligosaccharides - metabolism; PPCA; Recombinant Proteins - biosynthesis; Recombinant Proteins - genetics; Recombinant Proteins - isolation & purification; Recombinant Proteins - pharmacology; reticuloendothelial system; Spleen - drug effects; Spleen - pathology; Spodoptera - cytology; Spodoptera - virology; Vacuoles - enzymology; Vacuoles - pathology
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.03-0941fje

ABSTRACT Lysosomal storage diseases (LSDs) are monogenic disorders of metabolism caused by deficiency of hydrolytic enzymes. In several LSDs, cells of the reticuloendothelial (RE) system are the primary targets of the disease. Exogenous administration of recombinant enzymes overproduced in mammalian cells has proved effective for treating the systemic phenotype in nonneuropathic patients with LSDs. However, for the treatment of diseases with primary involvement of the RE system, the production of the therapeutic enzyme in insect cells could be an alternative and advantageous method because glycoproteins expressed in insect cells carry carbohydrates of the pauci‐mannose or core‐type. These recombinant enzymes are in principle already poised to be internalized by cells that express mannose receptors, including macrophages. Here, we demonstrate that three baculovirus‐expressed enzymes, protective protein/cathepsin A (PPCA), neuraminidase (Neu1), and β‐glucosidase, were readily taken up and restored lysosomal function in enzyme‐deficient mouse macrophages. The capacity of recombinant PPCA and Neu1 to clear the lysosomal storage in target cells was assessed in PPCA−/− mice, a model of galactosialidosis. Intravenously injected PPCA−/− mice efficiently internalized the corrective enzymes in resident macrophages of many organs. In addition, treated mice showed overall clearance of lysosomal storage in the most affected systemic organs, kidney, liver, and spleen. Our results suggest that ERT with baculovirus‐expressed enzymes might be an effective treatment for nonneuropathic patients with galactosialidosis and possibly for others with LSDs that primarily involve the RE system.