Skip Navigation



Human Molecular Genetics Advance Access published online on August 27, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm223
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow Supplementary Data
Right arrow All Versions of this Article:
16/22/2693    most recent
ddm223v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Fraldi, A.
Right arrow Articles by Hopwood, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Fraldi, A.
Right arrow Articles by Hopwood, J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Functional correction of CNS lesions in a MPS-IIIA mouse model by intracerebral AAV-mediated delivery of sulfamidase and SUMF1 genes

Alessandro Fraldi1,*, Kim Hemsley2, Allison Crawley2, Alessia Lombardi1, Adeline Lau2, Leanne Sutherland2, Alberto Auricchio1,3, Andrea Ballabio1,3 and John Hopwood2

1 Telethon Institute of Genetics and Medicine (TIGEM), 80131, Naples, Italy 2 Lysosomal Diseases Research Unit, Department of Genetic Medicine, Children, Youth and Women's Health Service, Adelaide 5006, Australia 3 Medical Genetics, Department of Pediatrics, Federico II University, Naples, Italy

* Correspondence to: Dr. Alessandro Fraldi, Telethon Institute of Genetics and Medicine (TIGEM), Via P. Castellino, 111 80131, Naples, Italy. Phone: + 39 (0)81 6132218, Fax: + 39 (0)81 5609877, Email: fraldi{at}tigem.it

Received June 25, 2007; Revised August 12, 2007; Accepted August 12, 2007

Mucopolysaccharidosis type IIIA (MPS-IIIA or Sanfilippo syndrome) is a lysosomal storage disorder (LSD) caused by the congenital deficiency of sulfamidase (SGSH) enzyme and consequent accumulation of partially-degraded heparan sulfate (HS) in lysosomes. The central nervous system (CNS) is the predominant site of tissue damage in MPS-IIIA. Here we describe a gene therapy approach for MPS-IIIA in a mouse model using recombinant adeno-associated virus serotype 5 (AAV2/5) as a vehicle to deliver therapeutic genes to the CNS. SUMF1 (SUlfatase Modifying Factor 1) exhibits an enhancing effect on sulfatase activity when co-expressed with sulfatases. Consistent with these findings, we demonstrated that co-delivery of SUMF1 and SGSH (via an AAV2/5-CMV-SGSH-IRES-SUMF1 vector) resulted in a synergistic increase in SGSH activity, both in primary neural cells and in murine brain. A study aimed at testing the therapeutic efficacy of simultaneous brain administration of SUMF1 and SGSH was then performed by injecting the lateral ventricles of newborn MPS-IIIA/normal mice with either AAV2/5-CMV-SGSH-IRES-SUMF1 or AAV2/5-CMV-GFP vectors. Widespread GFP expression was observed within the GFP-injected brain, while a stable and significant increase of SGSH activity was detected in several brain regions following SGSH-IRES-SUMF1 administration. Treatment with AAV2/5-CMV-SGSH-IRES-SUMF1 vectors resulted in a visible reduction in lysosomal storage and inflammatory markers in transduced brain regions. Finally, the MPS-IIIA mice treated with therapeutic genes displayed an improvement in both motor and cognitive function. Our results suggest that early treatment of CNS lesions by AAV-mediated intra-ventricular injection of both SGSH and SUMF1 genes may represent a feasible therapy for MPS-IIIA.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.