Infused Fc-tagged beta-glucuronidase crosses the placenta and produces clearance of storage in utero in mucopolysaccharidosis VII mice.

Abstract

Glycosaminoglycan storage begins in prenatal life in patients with mucopolysaccharidosis (MPS). In fact, prenatal hydrops is a common manifestation of MPS VII because of beta-glucuronidase (GUS) deficiency. One way to address prenatal storage might be to deliver the missing enzyme across the placenta into the fetal circulation. Maternal IgG is transported across the placenta by the neonatal Fc receptor (FcRn), which recognizes the Fc domain of IgG and mediates transcytosis from maternal to fetal circulation. We hypothesized that we could exploit this process to deliver corrective enzyme to the fetus. To test this hypothesis, the C-terminal fusion protein, GUS-Fc, was compared with native, untagged, recombinant GUS for clearance from the maternal circulation, delivery to the fetus, and reduction of lysosomal storage in offspring of MPS VII mice. We observed that GUS-Fc, infused into pregnant mothers on embryonic days 17 and 18, was transported across the placenta. Similarly infused untagged GUS was not delivered to the fetus. GUS-Fc plasma enzyme activity in newborn MPS VII mice was 1,000 times that seen after administration of untagged GUS and approximately 100 times that of untreated WT newborns. Reduced lysosomal storage in heart valves, liver, and spleen provided evidence that in utero enzyme replacement therapy with GUS-Fc targeted sites of storage in the MPS VII fetus. We hypothesize that this noninvasive approach could deliver the missing lysosomal enzyme to a fetus with any lysosomal storage disease. It might also provide a method for inducing immune tolerance to the missing enzyme or another foreign protein.

• Authors: Jeffrey H Grubb, Carole Vogler, Yun Tan, Gul N Shah, Amy F MacRae, 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. 105 Issue 24 Pg. 8375-80 (Jun 17 2008) ISSN: 1091-6490 [Electronic] United States
• PMID: 18544647 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Glycosaminoglycans
• Receptors, Fc
• Recombinant Fusion Proteins
• Glucuronidase

Topics

• Animals
• Female
• Glucuronidase (administration & dosage, pharmacokinetics, therapeutic use)
• Glycosaminoglycans (antagonists & inhibitors)
• Infusions, Parenteral
• Lysosomes (metabolism)
• Mice
• Mucopolysaccharidosis VII (prevention & control)
• Placenta (metabolism)
• Pregnancy
• Receptors, Fc (administration & dosage, therapeutic use)
• Recombinant Fusion Proteins (administration & dosage, pharmacokinetics, therapeutic use)
• Tissue Distribution
• Uterus