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Title: Systemic AAV-mediated gene therapy approach to treat CNS pathology in Mucopolysaccharidosis type IIIA
Author: Sorrentino, Nicolina Cristina
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2012
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Mucopolysaccharidosis type IIIA (MPS-IIIA) is a severe neurodegenerative lysosomal storage disorder (LSD) inherited as an autosomal recessive trait and caused by sulfamidase deficiency. Using somatic gene transfer, we demonstrated therapeutic efficacy of a novel low-invasive gene therapy approach to treat the brain pathology in MPS-IIIA. The therapeutic strategy is based on a chimeric sulfamidase engineered with both the signal peptide (sp) from the highly secreted iduronate-2-sulfatase (IDS) linked to its N-terminal end and the blood-brain barrier (BBB)-binding domain of apolipoproteinB (ApoB-BO) linked to its C-terminal end. These modifications allow the enzyme (i) to be highly secreted from the liver and (ii) to efficiently cross the BBB. A single intravascular administration of vectors, based on adena-associated virus (AAV) serotype 8, was performed in one-month old MPS-IIIA mice to efficiently target the liver and convert it in a factory organ for sustained systemic release of high levels of the modified sulfamidase. We show that while the 10Ssp replacement results in higher enzyme secretion, the addition of the ApoB-BO allows efficient BBB transcytosis and restoration of sulfamidase activity in the brain of treated MPS-IIIA mice to ~ 12-15% of the normal levels. This, in turn, results in reduction of pathological vacuolization,
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available