A highly secreted sulphamidase engineered to cross the blood-brain barrier corrects brain lesions of mice with mucopolysaccharidoses type IIIA

作者：Sorrentino Nicolina Cristina; D' Orsi Luca; Sambri Irene; Nusco Edoardo; Monaco Ciro; Spampanato Carmine; Polishchuk Elena; Saccone Paola; De Leonibus Elvira; Ballabio Andrea; Fraldi Alessandro^*

来源：EMBO Molecular Medicine, 2013, 5(5): 675-690.

DOI：10.1002/emmm.201202083

• blood-brain barrier
• CNS therapy
• lysosomal storage disorders
• MPS-IIIA
• sulphamidase

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

• 出版日期2013-5