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Cited by 25Lysosomal Storage Disorders ResearchVirus-based gene therapy researchRNA Interference and Gene Delivery

Broad Functional Correction of Molecular Impairments by Systemic Delivery of scAAVrh74-hSGSH Gene Delivery in MPS IIIA Mice

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Duncan, F Jason, Naughton, Bartholomew J, Zaraspe, Kimberly, Murrey, Darren A, Meadows, Aaron S, Clark, Kelly Reed, Newsom, David E, White, Peter +2 more·2015·Molecular Therapy
DOI 10.1038/mt.2015.9PMC PMC4395798
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Abstract

Mucopolysaccharidosis (MPS) IIIA is a neuropathic lysosomal storage disease caused by deficiency in N-sulfoglucosamine sulfohydrolase (SGSH). Genome-wide gene expression microarrays in MPS IIIA mice detected broad molecular abnormalities (greater than or equal to twofold, false discovery rate ≤10) in numerous transcripts (314) in the brain and blood (397). Importantly, 22 dysregulated blood transcripts are known to be enriched in the brain and linked to broad neuronal functions. To target the root cause, we used a self-complementary AAVrh74 vector to deliver the human SGSH gene into 4-6 weeks old MPS IIIA mice by an intravenous injection. The treatment resulted in global central nervous system (CNS) and widespread somatic restoration of SGSH activity, clearance of CNS and somatic glycosaminoglycan storage, improved behavior performance, and significantly extended survival. The scAAVrh74-hSGSH treatment also led to the correction of the majority of the transcriptional abnormalities in the brain (95.9%) and blood (97.7%), of which 182 and 290 transcripts were normalized in the brain and blood, respectively. These results demonstrate that a single systemic scAAVrh74-hSGSH delivery mediated efficient restoration of SGSH activity and resulted in a near complete correction of MPS IIIA molecular pathology. This study also demonstrates that blood transcriptional profiles reflect the biopathological status of MPS IIIA, and also respond well to effective treatments.

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  • A revised paradigm currently considers the use of muscle-specific promoters to prevent leaky expression, as well as systemic vector delivery for broader biodistribution via AAV9 and/or AAVrh74, which efficiently target both striated muscle and the CNS.

    “To overcome these limitations, a revised paradigm currently considers the use of muscle-specific promoters to prevent leaky expression, as well as systemic vector delivery for broader biodistribution via AAV9 and/or AAVrh74, which efficiently target both striated muscle and the CNS [123-125].”

    From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [125]

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Cited by

Sorted by citations

Authors
Duncan, F. J., Naughton, B. J., Zaraspe, K., Murrey, D. A., Meadows, A. S., Clark, K. R., Newsom, D. E., White, P., Fu, H., & McCarty, D. M.
Affiliations
Nationwide Children's Hospital (US)
Corresponding author
McCarty, Douglas M
ORCID
Venue
Molecular Therapy
Publisher
Elsevier BV
Published
2015-04
Volume
23
Issue
4
Pages
638-647
ISSN
1525-0016 (ISSN-L)
DOI
10.1038/mt.2015.9
PMC
PMC4395798
OpenAlex
W2085950278
Cited by
25
References
4
Citations by year
2025: 1 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 5 · 2019: 1 · 2017: 6 · 2016: 5 · 2015: 2
FWCI
3.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Therapy (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
mucopolysaccharidosis type IIIA, gene therapy, lysosomal storage disease, transcriptional dysregulation, blood transcriptome, brain transcriptome, survival, mouse model
MeSH terms
Dependovirus, Animals, Genetic Vectors, Humans, Hydrolases, Mice, Inbred C57BL, Mucopolysaccharidosis III, Genetic Therapy, Gene Transfer Techniques, Mice

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