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

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

doi:10.1016/j.omtm.2019.10.009

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

Mol Ther Methods Clin Dev. 2019 Oct 28:15:333-342. doi: 10.1016/j.omtm.2019.10.009. eCollection 2019 Dec 13.

Authors

Nicolina Cristina Sorrentino¹, Vincenzo Cacace¹, Maria De Risi¹, Veronica Maffia¹, Sandra Strollo¹, Novella Tedesco¹, Edoardo Nusco¹, Noemi Romagnoli², Domenico Ventrella², Yan Huang³, Nan Liu³, Susan L Kalled³, Vivian W Choi³, Elvira De Leonibus^{1

4}, Alessandro Fraldi^{1

5}

Affiliations

¹ Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, Pozzuoli, Naples, Italy.
² Department of Veterinary Medical Sciences, University of Bologna, Via Tolara di Sopra 50, Ozzano dell'Emilia, Bologna, Italy.
³ Takeda Pharmaceuticals, Cambridge, MA, USA.
⁴ Institute of Cellular Biology and Neurobiology (IBCN), National Research Council (CNR), Via Ramarini 32, Monterotondo, Rome, Italy.
⁵ Department of Translational Medicine, University of Naples "Federico II," Naples, Italy.

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.