Enhancing the Therapeutic Potential of Sulfamidase for the Treatment of Mucopolysaccharidosis IIIA
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...
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2019-12-01
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Series: | Molecular Therapy: Methods & Clinical Development |
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doaj-2d49ccd1afa048a9bc751084b264762d2020-11-25T00:29:23ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012019-12-0115333342Enhancing the Therapeutic Potential of Sulfamidase for the Treatment of Mucopolysaccharidosis IIIANicolina Cristina Sorrentino0Vincenzo Cacace1Maria De Risi2Veronica Maffia3Sandra Strollo4Novella Tedesco5Edoardo Nusco6Noemi Romagnoli7Domenico Ventrella8Yan Huang9Nan Liu10Susan L. Kalled11Vivian W. Choi12Elvira De Leonibus13Alessandro Fraldi14Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, Pozzuoli, Naples, Italy; Corresponding author: Nicolina Cristina Sorrentino, Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, Pozzuoli, Naples, Italy.Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, Pozzuoli, Naples, ItalyTelethon Institute of Genetics and Medicine, Via Campi Flegrei 34, Pozzuoli, Naples, ItalyTelethon Institute of Genetics and Medicine, Via Campi Flegrei 34, Pozzuoli, Naples, ItalyTelethon Institute of Genetics and Medicine, Via Campi Flegrei 34, Pozzuoli, Naples, ItalyTelethon Institute of Genetics and Medicine, Via Campi Flegrei 34, Pozzuoli, Naples, ItalyTelethon Institute of Genetics and Medicine, Via Campi Flegrei 34, Pozzuoli, Naples, ItalyDepartment of Veterinary Medical Sciences, University of Bologna, Via Tolara di Sopra 50, Ozzano dell’Emilia, Bologna, ItalyDepartment of Veterinary Medical Sciences, University of Bologna, Via Tolara di Sopra 50, Ozzano dell’Emilia, Bologna, ItalyTakeda Pharmaceuticals, Cambridge, MA, USATakeda Pharmaceuticals, Cambridge, MA, USATakeda Pharmaceuticals, Cambridge, MA, USATakeda Pharmaceuticals, Cambridge, MA, USATelethon Institute of Genetics and Medicine, Via Campi Flegrei 34, Pozzuoli, Naples, Italy; Institute of Cellular Biology and Neurobiology (IBCN), National Research Council (CNR), Via Ramarini 32, Monterotondo, Rome, Italy; Corresponding author: Elvira De Leonibus, Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, Pozzuoli, Naples, Italy.Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, Pozzuoli, Naples, Italy; Department of Translational Medicine, University of Naples “Federico II,” Naples, Italy; Corresponding author: Alessandro Fraldi, Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, Pozzuoli, Naples, Italy.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.http://www.sciencedirect.com/science/article/pii/S2329050119301172 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Enhancing the Therapeutic Potential of Sulfamidase for the Treatment of Mucopolysaccharidosis IIIA Molecular Therapy: Methods & Clinical Development |
author_facet |
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 |
author_sort |
Nicolina Cristina Sorrentino |
title |
Enhancing the Therapeutic Potential of Sulfamidase for the Treatment of Mucopolysaccharidosis IIIA |
title_short |
Enhancing the Therapeutic Potential of Sulfamidase for the Treatment of Mucopolysaccharidosis IIIA |
title_full |
Enhancing the Therapeutic Potential of Sulfamidase for the Treatment of Mucopolysaccharidosis IIIA |
title_fullStr |
Enhancing the Therapeutic Potential of Sulfamidase for the Treatment of Mucopolysaccharidosis IIIA |
title_full_unstemmed |
Enhancing the Therapeutic Potential of Sulfamidase for the Treatment of Mucopolysaccharidosis IIIA |
title_sort |
enhancing the therapeutic potential of sulfamidase for the treatment of mucopolysaccharidosis iiia |
publisher |
Elsevier |
series |
Molecular Therapy: Methods & Clinical Development |
issn |
2329-0501 |
publishDate |
2019-12-01 |
description |
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. |
url |
http://www.sciencedirect.com/science/article/pii/S2329050119301172 |
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