1. ¹Department of Neurology, Laboratory of Protein Misfolding Disorders, University of Texas Medical Branch, Galveston, Texas, USA
2. ²Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Doisy Research Center, St. Louis, Missouri, USA
3. ³Geriatric Research, Education and Clinical Center, Veterans Affairs Medical Center, St. Louis, Missouri, USA
4. ⁴Department of Internal Medicine, Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, USA

Correspondence: Edward A. Doisy, Department of Biochemistry, 1100 S. Grand Boulevard, Doisy Research Center, Room 533, St. Louis, Missouri 63104, USA. E-mail: slyws@slu.edu; William A. Banks, Geriatric Research, Education and Clinical Center, Veterans Affairs Medical Center, 915 N. Grand Boulevard, St. Louis, Missouri 63106, USA. E-mail: bankswa@slu.edu

Received 14 February 2008; Accepted 28 March 2008; Published online 29 April 2008.

Abstract

Mucopolysaccharidosis type IIIA (MPS IIIA), which is a lysosomal storage disorder (LSD) caused by inherited deficiency of sulfamidase, is characterized by severe, progressive central nervous system (CNS) dysfunction. Enzyme replacement therapy (ERT) to treat CNS storage is challenging, because the access of enzymes to the brain is restricted by the blood–brain barrier (BBB). In a prior study, we found that phosphorylated -glucuronidase (P-GUS) could be transcytosed across the BBB in newborn mice by the mannose 6-phosphate (M6P) receptor. In order to determine whether sulfamidase can utilize this pathway, we examined brain influx and the specificity of uptake of sulfamidase after intravenous (IV) injection in 2-day-old and 8-week-old mice. [¹³¹I]Sulfamidase was transported across the BBB in neonates at rates higher than that of simultaneously injected [¹²⁵I]albumin. In contrast, the transport of [¹³¹I]sulfamidase was negligible in 8-week-old mice, thereby showing that the BBB transport mechanism is developmentally downregulated. Capillary depletion revealed that 83.7% of the [¹³¹I]sulfamidase taken up by the brain was in the parenchyma, demonstrating transfer across the capillary wall. The uptake of [¹³¹I]sulfamidase into the brain was significantly reduced by co-injections of M6P and P-GUS. That is, the transport of sulfamidase into the brain parenchyma in early postnatal life is mediated by the M6P receptor, which is shared with P-GUS and is likely accessible to other M6P-containing lysosomal enzymes.