Intranasal Adeno-Associated Virus Mediated Gene Delivery and Expression of Human Iduronidase in the Central Nervous System: A Noninvasive and Effective Approach for Prevention of Neurologic Disease in Mucopolysaccharidosis Type I
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Mucopolysaccharidosis type I (MPS I) is a progressive, multi-systemic, inherited metabolic disease caused by deficiency of α-L-iduronidase (IDUA). Current treatments for this disease are ineffective in treating central nervous system (CNS) disease due to the inability of lysosomal enzymes to traverse the blood–brain barrier. A noninvasive and effective approach was taken in the treatment of CNS disease by intranasal administration of an IDUA-encoding adeno-associated virus serotype 9 (AAV9) vector. Adult IDUA-deficient mice aged 3 months were instilled intranasally with AAV9-IDUA vector. Animals sacrificed 5 months post instillation exhibited IDUA enzyme activity levels that were up to 50-fold that of wild-type mice in the olfactory bulb, with wild-type levels of enzyme restored in all other parts of the brain. Intranasal treatment with AAV9-IDUA also resulted in the reduction of tissue glycosaminoglycan storage materials in the brain. There was strong IDUA immunofluorescence staining of tissue sections observed in the nasal epithelium and olfactory bulb, but there was no evidence of the presence of transduced cells in other portions of the brain. This indicates that reduction of storage materials most likely occurred as a result of enzyme diffusion from the olfactory bulb and the nasal epithelium into deeper areas of the brain. At 8 months of age, neurocognitive testing using the Barnes maze to assess spatial navigation demonstrated that treated IDUA-deficient mice were no different from normal control animals, while untreated IDUA-deficient mice exhibited significant learning and navigation deficits. This novel, noninvasive strategy for intranasal AAV9-IDUA instillation could potentially be used to treat CNS manifestations of human MPS I.
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Intranasal delivery of AAV9 via the nasal cavity in mice for mucopolysaccharidosis I resulted in widespread detection of transgene activity across the CNS.
“an additional non-surgical route—intranasal—has been tested delivering AAV9 via the nasal cavity in mice for mucopolysaccharidosis I, resulting in widespread detection of the transgene activity across the CNS”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [96]
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AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease
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- Authors
- Belur, L. R., Temme, A., Podetz-Pedersen, K. M., Riedl, M., Vulchanova, L., Robinson, N., Hanson, L. R., Kozarsky, K. F., Orchard, P. J., Frey, W. H., Low, W. C., & McIvor, R. S.
- Affiliations
- University of Minnesota (US)
- Regions Hospital (US)
- Regenxbio (United States) (US)
- ORCID
- Venue
- Human Gene Therapy
- Publisher
- SAGE Publications
- Published
- 2017-07
- Volume
- 28
- Issue
- 7
- Pages
- 576-587
- ISSN
- 1043-0342 (ISSN-L)
- 1557-7422
- PMC
- PMC5549804
- OpenAlex
- W2611199202
- Cited by
- 67
- References
- 60
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 8 · 2023: 3 · 2022: 15 · 2021: 11 · 2020: 12 · 2019: 4 · 2018: 3 · 2017: 1
- FWCI
- 4.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Human Gene Therapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Pennsylvania
- University of Minnesota
- 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 I, alpha-L-iduronidase, AAV9 vector, intranasal gene delivery, central nervous system gene therapy, blood-brain barrier, olfactory bulb, nasal epithelium, glycosaminoglycan storage, enzyme diffusion, neurocognitive impairment, spatial navigation
- MeSH terms
- Dependovirus, Administration, Intranasal, Animals, Central Nervous System, Cognition, Humans, Iduronidase, Mucopolysaccharidosis I, Lysosomes, Nasal Mucosa, Nervous System Diseases, Neurons, Olfactory Bulb, Transduction, Genetic, Gene Transfer Techniques, Green Fluorescent Proteins, Mice
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