ArticleMolecular therapy : the journal of the American Society of Gene Therapy2018
Overcoming Limitations Inherent in Sulfamidase to Improve Mucopolysaccharidosis IIIA Gene Therapy.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 17 citations in OpenAlex.
- Current trends in gene therapy to treat inherited disorders of the brain.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Endothelial and neuronal engagement by AAV-BR1 gene therapy alleviates neurological symptoms and lipid deposition in a mouse model of Niemann-Pick type C2.Fluids and barriers of the CNS · 2025Article
- Intracerebral lentiviral ABCD1 gene therapy in an early disease onset ALD mouse model.Gene therapy · 2023Article
- Mammalian Sulfatases: Biochemistry, Disease Manifestation, and Therapy.International journal of molecular sciences · 2022Review
- Gene-based therapeutics for rare genetic neurodevelopmental psychiatric disorders.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Review
- Evaluation of artificial signal peptides for secretion of two lysosomal enzymes in CHO cells.The Biochemical journal · 2021Article
- Enhancing the Therapeutic Potential of Sulfamidase for the Treatment of Mucopolysaccharidosis IIIA.Molecular therapy. Methods & clinical development · 2019Article
- Intravenous delivery of a chemically modified sulfamidase efficiently reduces heparan sulfate storage and brain pathology in mucopolysaccharidosis IIIA mice.Molecular genetics and metabolism reports · 2019Article
- An Engineered Galactosylceramidase Construct Improves AAV Gene Therapy for Krabbe Disease in Twitcher Mice.Human gene therapy · 2019Article
- AAV-Mediated Progranulin Delivery to a Mouse Model of Progranulin Deficiency Causes T Cell-Mediated Toxicity.Molecular therapy : the journal of the American Society of Gene Therapy · 2019Article
- Recent trends in mucopolysaccharidosis research.Journal of human genetics · 2019Review
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Sulfamidase (SGSH) deficiency causes mucopolysaccharidosis type IIIA (MPS IIIA), a lysosomal storage disease (LSD) that affects the CNS. In earlier work in LSD mice and dog models, we exploited the utility of adeno-associated viruses (AAVs) to transduce brain ventricular lining cells (ependyma) for secretion of lysosomal hydrolases into the cerebrospinal fluid (CSF), with subsequent distribution of enzyme throughout the brain resulting in improved cognition and extending lifespan. A critical feature of this approach is efficient secretion of the expressed enzyme from transduced cells, for delivery by CSF to nontransduced cells. Surprisingly, we found that SGSH was poorly secreted from cells, resulting in retention of the expressed product. Using site-directed mutagenesis of native SGSH, we identified an improved secretion variant that also displayed enhanced uptake properties that were mannose-6-phosphate receptor independent. In studies in MPS IIIA-deficient mice, ependymal transduction with AAVs expressing variant SGSH improved spatial learning and reduced memory deficits, substrate accumulation, and astrogliosis. Secondary lysosomal enzyme elevations in the CSF and brain parenchyma were also resolved. In contrast, ependymal transduction with AAVs expressing wild-type SGSH had significantly lower CSF SGSH levels and limited impacts on behavior. These results demonstrate the utility of a previously undescribed SGSH variant for improved MPS IIIA brain gene therapy.
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