A highly secreted sulphamidase engineered to cross the blood-brain barrier corrects brain lesions of mice with mucopolysaccharidoses type IIIA
Article first published online: 9 APR 2013
Copyright © 2013 EMBO Molecular Medicine
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 5, Issue 5, pages 675–690, May 2013
How to Cite
Sorrentino, N. C., D'Orsi, L., Sambri, I., Nusco, E., Monaco, C., Spampanato, C., Polishchuk, E., Saccone, P., De Leonibus, E., Ballabio, A. and Fraldi, A. (2013), A highly secreted sulphamidase engineered to cross the blood-brain barrier corrects brain lesions of mice with mucopolysaccharidoses type IIIA. EMBO Mol Med, 5: 675–690. doi: 10.1002/emmm.201202083
- Issue published online: 7 MAY 2013
- Article first published online: 9 APR 2013
- Manuscript Revised: 20 FEB 2013
- Manuscript Accepted: 20 FEB 2013
- Manuscript Received: 26 SEP 2012
- American MPS Society. Grant Number: A.F.
- Genzyme. Grant Numbers: A.F., A.B.
- Italian Telethon Foundation. Grant Number: TGM11MT5, grant to A.F.
- blood-brain barrier;
- CNS therapy;
- lysosomal storage disorders;
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.
See accompanying article emmm.201302668