Journal
MOLECULAR THERAPY
Volume 16, Issue 7, Pages 1261-1266Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/mt.2008.84
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Funding
- NIA NIH HHS [R01 AG029839] Funding Source: Medline
- NIGMS NIH HHS [R01 GM034182, GM34182, R01 GM034182-22] Funding Source: Medline
- NINDS NIH HHS [R01 NS041863, R01NS41863, R01 NS041863-05] Funding Source: Medline
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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 beta-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. [I-131] Sulfamidase was transported across the BBB in neonates at rates higher than that of simultaneously injected [I-125] albumin. In contrast, the transport of [I-131] 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 [I-131] sulfamidase taken up by the brain was in the parenchyma, demonstrating transfer across the capillary wall. The uptake of [I-131] 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.
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