Human Molecular Genetics Advance Access originally published online on August 27, 2007
Human Molecular Genetics 2007 16(22):2693-2702; doi:10.1093/hmg/ddm223
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Functional correction of CNS lesions in an MPS-IIIA mouse model by intracerebral AAV-mediated delivery of sulfamidase and SUMF1 genes
1 Telethon Institute of Genetics and Medicine (TIGEM), 80131 Naples, Italy, 2 Department of Genetic Medicine, Children, Youth and Women’s Health Service, Lysosomal Diseases Research Unit, Adelaide 5006, Australia, 3 Medical Genetics, Department of Pediatrics, Federico II University, Naples, Italy
* To whom correspondence should be addressed at: Telethon Institute of Genetics and Medicine (TIGEM), Via P. Castellino, 111, 80131 Naples, Italy. Tel: +39 0816132218; Fax: +39 0815609877; 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 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, and 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 functions. Our results suggest that early treatment of CNS lesions by AAV-mediated intraventricular 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.