Enhancing the Therapeutic Potential of Sulfamidase for the Treatment of Mucopolysaccharidosis IIIA.

Abstract

Mucopolysaccharidosis type IIIA (MPS-IIIA) is a lysosomal storage disorder (LSD) caused by inherited defect of sulfamidase, a lysosomal sulfatase. MPS-IIIA is one of the most common and severe forms of LSDs with CNS involvement. Presently there is no cure. Here we have developed a new gene delivery approach for the treatment of MPS-IIIA based on the use of a modified version of sulfamidase expression cassette. This cassette encodes both a chimeric sulfamidase containing an alternative signal peptide (sp) to improve enzyme secretion and sulfatase-modifying factor 1 (SUMF1) to increase sulfamidase post-translational activation rate. We demonstrate that improved secretion and increased activation of sulfamidase act synergistically to enhance enzyme biodistribution in wild-type (WT) pigs upon intrathecal adeno-associated virus serotype 9 (AAV9)-mediated gene delivery. Translating such gene delivery strategy to a mouse model of MPS-IIIA results in a rescue of brain pathology, including memory deficit, as well as improvement in somatic tissues. These data may pave the way for developing effective gene delivery replacement protocols for the treatment of MPS-IIIA patients.

• Authors: Nicolina Cristina Sorrentino, Vincenzo Cacace, Maria De Risi, Veronica Maffia, Sandra Strollo, Novella Tedesco, Edoardo Nusco, Noemi Romagnoli, Domenico Ventrella, Yan Huang, Nan Liu, Susan L Kalled, Vivian W Choi, Elvira De Leonibus, Alessandro Fraldi
• Journal: Molecular therapy. Methods & clinical development (Mol Ther Methods Clin Dev) Vol. 15 Pg. 333-342 (Dec 13 2019) ISSN: 2329-0501 [Print] United States
• PMID: 31788497 (Publication Type: Journal Article)
• Copyright: © 2019 The Authors.