Reduction in Brain Heparan Sulfate with Systemic Administration of an IgG Trojan Horse-Sulfamidase Fusion Protein in the Mucopolysaccharidosis Type IIIA Mouse
| Autor: | Ruben J. Boado, Jeff Zhiqiang Lu, William M. Pardridge, Eric Ka-Wai Hui |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Hydrolases Recombinant Fusion Proteins Pharmaceutical Science Transferrin receptor Blood–brain barrier Inclusion bodies Immunoglobulin G 03 medical and health sciences chemistry.chemical_compound Mice Mucopolysaccharidosis III Drug Discovery Receptors Transferrin medicine Animals Humans Mucopolysaccharidosis Type IIIA Mice Knockout biology Antibodies Monoclonal Brain Heparan sulfate Fusion protein Molecular biology Disease Models Animal 030104 developmental biology medicine.anatomical_structure chemistry Liver biology.protein Molecular Medicine Female Heparitin Sulfate |
| Zdroj: | Molecular pharmaceutics. 15(2) |
| ISSN: | 1543-8392 |
| Popis: | Mucopolysaccharidosis Type IIIA (MPSIIIA), also known as Sanfilippo A syndrome, is an inherited neurodegenerative disease caused by mutations in the lysosomal enzyme, N-sulfoglucosamine sulfohydrolase (SGSH), also known as sulfamidase. Mutations in the SGSH enzyme, the only mammalian heparan N-sulfatase, cause accumulation of lysosomal inclusion bodies in brain cells comprising heparan sulfate (HS) glycosaminoglycans (GAGs). Treatment of MPSIIIA with intravenous recombinant SGSH is not possible because this large molecule does not cross the blood-brain barrier (BBB). BBB penetration by SGSH was enabled in the present study by re-engineering this enzyme as an IgG-SGSH fusion protein, where the IgG domain is a chimeric monoclonal antibody (mAb) against the mouse transferrin receptor (TfR), designated the cTfRMAb. The IgG domain of the fusion protein acts as a molecular Trojan horse to deliver the enzyme into brain via transport on the endogenous BBB TfR. The cTfRMAb-SGSH fusion protein bound to the mouse TfR with high affinity, ED |
| Databáze: | OpenAIRE |
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