Glycosylation-independent targeting enhances enzyme delivery to lysosomes and decreases storage in mucopolysaccharidosis type VII mice.

Abstract

Enzyme-replacement therapy is an established means of treating lysosomal storage diseases. Infused therapeutic enzymes are targeted to lysosomes of affected cells by interactions with cell-surface receptors that recognize carbohydrate moieties, such as mannose and mannose 6-phosphate, on the enzymes. We have tested an alternative, peptide-based targeting system for delivery of enzymes to lysosomes in a murine mucopolysaccharidosis type VII (MPS VII) model. This strategy depends on the interaction of a fragment of insulin-like growth factor II (IGF-II), with the IGF-II binding site on the bifunctional, IGF-II cation-independent mannose 6-phosphate receptor. A chimeric protein containing a portion of mature human IGF-II fused to the C terminus of human beta-glucuronidase was taken up by MPS VII fibroblasts in a mannose 6-phosphate-independent manner, and its uptake was inhibited by the addition of IGF-II. Furthermore, the tagged enzyme was delivered effectively to clinically significant tissues in MPS VII mice and was effective in reversing the storage pathology. The tagged enzyme was able to reduce storage in glomerular podocytes and osteoblasts at a dose at which untagged enzyme was much less effective. This peptide-based, glycosylation-independent lysosomal targeting system may enhance enzyme-replacement therapy for certain human lysosomal storage diseases.

• Authors: Jonathan H LeBowitz, Jeffrey H Grubb, John A Maga, Deborah H Schmiel, Carole Vogler, William S Sly
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 101 Issue 9 Pg. 3083-8 (Mar 02 2004) ISSN: 0027-8424 [Print] United States
• PMID: 14976248 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Enzymes
• Recombinant Proteins
• Insulin-Like Growth Factor II
• Glucuronidase

Topics

• Animals
• CHO Cells
• Cricetinae
• Disease Models, Animal
• Enzyme Therapy
• Enzymes (genetics)
• Genetic Therapy
• Glucuronidase (genetics, therapeutic use)
• Humans
• Insulin-Like Growth Factor II (genetics)
• Lysosomes (enzymology)
• Mice
• Mucopolysaccharidosis VII (drug therapy)
• Mutagenesis, Insertional
• Recombinant Proteins (metabolism)
• Transfection