title: 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.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
authors.forename: Nicolina Cristina
authors.initials: NC
authors.lastname: Sorrentino
authors.forename: Luca
authors.initials: L
authors.lastname: D'Orsi
authors.forename: Irene
authors.initials: I
authors.lastname: Sambri
authors.forename: Edoardo
authors.initials: E
authors.lastname: Nusco
authors.forename: Ciro
authors.initials: C
authors.lastname: Monaco
authors.forename: Carmine
authors.initials: C
authors.lastname: Spampanato
authors.forename: Elena
authors.initials: E
authors.lastname: Polishchuk
authors.forename: Paola
authors.initials: P
authors.lastname: Saccone
authors.forename: Elvira
authors.initials: E
authors.lastname: De Leonibus
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fraldi
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000737:chemistry / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000473:pathology / Q000502:physiology*; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D007066:Iduronate Sulfatase / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009084:Mucopolysaccharidosis III / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D057900:Transcytosis
chemical_list: D001055:Apolipoproteins B; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D007066:Iduronate Sulfatase; D012697:Serine Endopeptidases; C026515:type I signal peptidase