A highly secreted sulphamidase engineered to cross the blood-brain barrier corrects brain lesions of mice with mucopolysaccharidoses type IIIA.

Abstract

Mucopolysaccharidoses type IIIA (MPS-IIIA) is a neurodegenerative lysosomal storage disorder (LSD) caused by inherited defects of the sulphamidase gene. Here, we used a systemic gene transfer approach to demonstrate the therapeutic efficacy of a chimeric sulphamidase, which was engineered by adding the signal peptide (sp) from the highly secreted iduronate-2-sulphatase (IDS) and the blood-brain barrier (BBB)-binding domain (BD) from the Apolipoprotein B (ApoB-BD). A single intravascular administration of AAV2/8 carrying the modified sulphamidase was performed in adult MPS-IIIA mice in order to target the liver and convert it to a factory organ for sustained systemic release of the modified sulphamidase. We showed that while the IDS sp replacement results in increased enzyme secretion, the addition of the ApoB-BD allows efficient BBB transcytosis and restoration of sulphamidase activity in the brain of treated mice. This, in turn, resulted in an overall improvement of brain pathology and recovery of a normal behavioural phenotype. Our results provide a novel feasible strategy to develop minimally invasive therapies for the treatment of brain pathology in MPS-IIIA and other neurodegenerative LSDs.

• Authors: Nicolina Cristina Sorrentino, Luca D'Orsi, Irene Sambri, Edoardo Nusco, Ciro Monaco, Carmine Spampanato, Elena Polishchuk, Paola Saccone, Elvira De Leonibus, Andrea Ballabio, Alessandro Fraldi
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 5 Issue 5 Pg. 675-90 (May 2013) ISSN: 1757-4684 [Electronic] England
• PMID: 23568409 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

Chemical References

• Apolipoproteins B
• Membrane Proteins
• Recombinant Fusion Proteins
• Iduronate Sulfatase
• Serine Endopeptidases
• type I signal peptidase

Topics

• Animals
• Apolipoproteins B (chemistry, metabolism)
• Blood-Brain Barrier (metabolism)
• Brain (pathology, physiology)
• Cell Line
• Dependovirus (genetics)
• Disease Models, Animal
• Gene Transfer Techniques
• Genetic Vectors (genetics, metabolism)
• Iduronate Sulfatase (genetics, metabolism)
• Liver (metabolism)
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mucopolysaccharidosis III (enzymology, genetics, pathology)
• Phenotype
• Protein Engineering
• Protein Structure, Tertiary
• Recombinant Fusion Proteins (biosynthesis, genetics)
• Serine Endopeptidases (genetics, metabolism)
• Transcytosis