Reversal of lysosomal storage in brain of adult MPS-I mice with intravenous Trojan horse-iduronidase fusion protein

Mol Pharm. 2011 Aug 1;8(4):1342-50. doi: 10.1021/mp200136x. Epub 2011 Jun 17.


A mouse model of mucopolysaccharidosis (MPS) type I, which is null for the lysosomal enzyme, α-L-iduronidase (IDUA), is treated with intravenous, receptor-mediated enzyme replacement therapy of the brain. Murine IDUA, which does not cross the blood-brain barrier, is re-engineered for targeting to the brain as an IgG-enzyme fusion protein. The amino terminus of mature IDUA is fused to the carboxyl terminus of the heavy chain of a chimeric monoclonal antibody (mAb) against the murine transferrin receptor (TfR), and this fusion protein is designated cTfRMAb-IDUA. The cTfRMAb part of the fusion protein acts as a molecular Trojan horse to ferry the fused IDUA across the BBB and neuronal cell membrane via transport on the TfR. The IDUA enzyme activity of the fusion protein, 776 ± 79 units/μg protein, is comparable to recombinant IDUA. MPSI null mice, 6-8 months of age, were treated iv twice a week for 8 weeks with either saline or 1 mg/kg cTfRMAb-IDUA. The glycosoaminoglycan levels in liver, spleen, heart, and kidney were reduced by >95%, 80%, 36%, and 20%, respectively. Lysosomal inclusion bodies in the brain were quantitated from semithin sections stained with o-toluidine blue and normalized per 100 nucleoli per brain section. Treatment of the MPSI mice with the cTfRMAb-IDUA reduced intracellular lysosomal inclusion bodies by 73% in brain, as compared to the MPSI mice treated with saline. In conclusion, the reversal of pre-existing neural pathology in the brain of MPSI mice is possible with receptor-mediated enzyme replacement therapy of the brain.

MeSH terms

  • 3T3 Cells
  • Animals
  • Antibodies, Monoclonal / genetics
  • Antibodies, Monoclonal / metabolism*
  • Blood-Brain Barrier / metabolism
  • Blotting, Western
  • Brain / drug effects
  • Brain / metabolism*
  • Brain / pathology
  • COS Cells
  • Chlorocebus aethiops
  • Electrophoresis, Polyacrylamide Gel
  • Enzyme-Linked Immunosorbent Assay
  • Glycosaminoglycans / metabolism
  • Iduronidase / genetics
  • Iduronidase / metabolism*
  • Mice
  • Mucopolysaccharidosis I / drug therapy*
  • Receptors, Transferrin / immunology
  • Receptors, Transferrin / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism*
  • Recombinant Fusion Proteins / therapeutic use*


  • Antibodies, Monoclonal
  • Glycosaminoglycans
  • Receptors, Transferrin
  • Recombinant Fusion Proteins
  • Iduronidase