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Non-invasive intravenous administration of AAV9 transducing iduronate sulfatase leads to global metabolic correction and prevention of neurologic deficits in a mouse model of Hunter syndrome

Hunter syndrome is a rare x-linked recessive genetic disorder that affects lysosomal metabolism due to deficiency of iduronate-2-sulfatase (IDS), with subsequent accumulation of glycosaminoglycans heparan and dermatan sulfates (GAG). Enzyme replacement therapy is the only FDA-approved remedy and is...

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Autores principales: Laoharawee, Kanut, Podetz-Pedersen, Kelly M., Nguyen, Tam T., Singh, Sajya M., Smith, Miles C., Belur, Lalitha R., Low, Walter C., Kozarsky, Karen F., McIvor, R. Scott
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9871739/
https://www.ncbi.nlm.nih.gov/pubmed/36704405
http://dx.doi.org/10.1016/j.ymgmr.2023.100956
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author Laoharawee, Kanut
Podetz-Pedersen, Kelly M.
Nguyen, Tam T.
Singh, Sajya M.
Smith, Miles C.
Belur, Lalitha R.
Low, Walter C.
Kozarsky, Karen F.
McIvor, R. Scott
author_facet Laoharawee, Kanut
Podetz-Pedersen, Kelly M.
Nguyen, Tam T.
Singh, Sajya M.
Smith, Miles C.
Belur, Lalitha R.
Low, Walter C.
Kozarsky, Karen F.
McIvor, R. Scott
author_sort Laoharawee, Kanut
collection PubMed
description Hunter syndrome is a rare x-linked recessive genetic disorder that affects lysosomal metabolism due to deficiency of iduronate-2-sulfatase (IDS), with subsequent accumulation of glycosaminoglycans heparan and dermatan sulfates (GAG). Enzyme replacement therapy is the only FDA-approved remedy and is an expensive life-time treatment that alleviates some symptoms of the disease without neurocognitive benefit. We previously reported successful treatment in a mouse model of mucopolysaccharidosis type II (MPS II) using adeno-associated viral vector serotype 9 encoding human IDS (AAV9.hIDS) via intracerebroventricular injection. As a less invasive and more straightforward procedure, here we report intravenously administered AAV9.hIDS in a mouse model of MPS II. In animals administered 1.5 × 10(12) vg of AAV9.hIDS at 2 months of age, we observed supraphysiological levels of IDS enzyme activity in the circulation (up to 9100-fold higher than wild-type), in the tested peripheral organs (up to 560-fold higher than wild-type), but only 4% to 50% of wild type levels in the CNS. GAG levels were normalized on both sides of the blood-brain-barrier (BBB) in most of tissues tested. Despite low levels of the IDS observed in the CNS, this treatment prevented neurocognitive decline as shown by testing in the Barnes maze and by fear conditioning. This study demonstrates that a single dose of IV-administered AAV9.hIDS may be an effective and non-invasive procedure to treat MPS II that benefits both sides of the BBB, with implications for potential use of IV-administered AAV9 for other neuronopathic lysosomal diseases.
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spelling pubmed-98717392023-01-25 Non-invasive intravenous administration of AAV9 transducing iduronate sulfatase leads to global metabolic correction and prevention of neurologic deficits in a mouse model of Hunter syndrome Laoharawee, Kanut Podetz-Pedersen, Kelly M. Nguyen, Tam T. Singh, Sajya M. Smith, Miles C. Belur, Lalitha R. Low, Walter C. Kozarsky, Karen F. McIvor, R. Scott Mol Genet Metab Rep Research Paper Hunter syndrome is a rare x-linked recessive genetic disorder that affects lysosomal metabolism due to deficiency of iduronate-2-sulfatase (IDS), with subsequent accumulation of glycosaminoglycans heparan and dermatan sulfates (GAG). Enzyme replacement therapy is the only FDA-approved remedy and is an expensive life-time treatment that alleviates some symptoms of the disease without neurocognitive benefit. We previously reported successful treatment in a mouse model of mucopolysaccharidosis type II (MPS II) using adeno-associated viral vector serotype 9 encoding human IDS (AAV9.hIDS) via intracerebroventricular injection. As a less invasive and more straightforward procedure, here we report intravenously administered AAV9.hIDS in a mouse model of MPS II. In animals administered 1.5 × 10(12) vg of AAV9.hIDS at 2 months of age, we observed supraphysiological levels of IDS enzyme activity in the circulation (up to 9100-fold higher than wild-type), in the tested peripheral organs (up to 560-fold higher than wild-type), but only 4% to 50% of wild type levels in the CNS. GAG levels were normalized on both sides of the blood-brain-barrier (BBB) in most of tissues tested. Despite low levels of the IDS observed in the CNS, this treatment prevented neurocognitive decline as shown by testing in the Barnes maze and by fear conditioning. This study demonstrates that a single dose of IV-administered AAV9.hIDS may be an effective and non-invasive procedure to treat MPS II that benefits both sides of the BBB, with implications for potential use of IV-administered AAV9 for other neuronopathic lysosomal diseases. Elsevier 2023-01-20 /pmc/articles/PMC9871739/ /pubmed/36704405 http://dx.doi.org/10.1016/j.ymgmr.2023.100956 Text en © 2023 Published by Elsevier Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Laoharawee, Kanut
Podetz-Pedersen, Kelly M.
Nguyen, Tam T.
Singh, Sajya M.
Smith, Miles C.
Belur, Lalitha R.
Low, Walter C.
Kozarsky, Karen F.
McIvor, R. Scott
Non-invasive intravenous administration of AAV9 transducing iduronate sulfatase leads to global metabolic correction and prevention of neurologic deficits in a mouse model of Hunter syndrome
title Non-invasive intravenous administration of AAV9 transducing iduronate sulfatase leads to global metabolic correction and prevention of neurologic deficits in a mouse model of Hunter syndrome
title_full Non-invasive intravenous administration of AAV9 transducing iduronate sulfatase leads to global metabolic correction and prevention of neurologic deficits in a mouse model of Hunter syndrome
title_fullStr Non-invasive intravenous administration of AAV9 transducing iduronate sulfatase leads to global metabolic correction and prevention of neurologic deficits in a mouse model of Hunter syndrome
title_full_unstemmed Non-invasive intravenous administration of AAV9 transducing iduronate sulfatase leads to global metabolic correction and prevention of neurologic deficits in a mouse model of Hunter syndrome
title_short Non-invasive intravenous administration of AAV9 transducing iduronate sulfatase leads to global metabolic correction and prevention of neurologic deficits in a mouse model of Hunter syndrome
title_sort non-invasive intravenous administration of aav9 transducing iduronate sulfatase leads to global metabolic correction and prevention of neurologic deficits in a mouse model of hunter syndrome
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9871739/
https://www.ncbi.nlm.nih.gov/pubmed/36704405
http://dx.doi.org/10.1016/j.ymgmr.2023.100956
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