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Intravenous delivery for treatment of mucopolysaccharidosis type I: A comparison of AAV serotypes 9 and rh10

Mucopolysaccharidosis type I (MPS I) is an inherited metabolic disorder caused by deficiency of alpha-L-iduronidase (IDUA), resulting in accumulation of heparan and dermatan sulfate glycosaminoglycans (GAGs). Individuals with the most severe form of the disease (Hurler syndrome) suffer from neurodeg...

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Autores principales: Belur, Lalitha R., Podetz-Pedersen, Kelly M., Tran, Thuy An, Mesick, Joshua A., Singh, Nathaniel M., Riedl, Maureen, Vulchanova, Lucy, Kozarsky, Karen F., McIvor, R. Scott
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242863/
https://www.ncbi.nlm.nih.gov/pubmed/32461912
http://dx.doi.org/10.1016/j.ymgmr.2020.100604
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author Belur, Lalitha R.
Podetz-Pedersen, Kelly M.
Tran, Thuy An
Mesick, Joshua A.
Singh, Nathaniel M.
Riedl, Maureen
Vulchanova, Lucy
Kozarsky, Karen F.
McIvor, R. Scott
author_facet Belur, Lalitha R.
Podetz-Pedersen, Kelly M.
Tran, Thuy An
Mesick, Joshua A.
Singh, Nathaniel M.
Riedl, Maureen
Vulchanova, Lucy
Kozarsky, Karen F.
McIvor, R. Scott
author_sort Belur, Lalitha R.
collection PubMed
description Mucopolysaccharidosis type I (MPS I) is an inherited metabolic disorder caused by deficiency of alpha-L-iduronidase (IDUA), resulting in accumulation of heparan and dermatan sulfate glycosaminoglycans (GAGs). Individuals with the most severe form of the disease (Hurler syndrome) suffer from neurodegeneration, intellectual disability, and death by age 10. Current treatments for this disease include allogeneic hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT). However, these treatments do not address CNS manifestations of the disease. In this study we compared the ability of intravenously administered AAV serotypes 9 and rh10 (AAV9 and AAVrh10) for delivery and expression of the IDUA gene in the CNS. Adult C57BL/6 MPS I mice were infused intravenously with either AAV9 or AAVrh10 vector encoding the human IDUA gene. Treated animals demonstrated supraphysiological levels and widespread restoration of IDUA enzyme activity in the plasma and all organs including the CNS. High levels of IDUA enzyme activity were observed in the plasma, brain and spinal cord ranging from 10 to 100-fold higher than heterozygote controls, while levels in peripheral organs were also high, ranging from 1000 to 10,000-fold higher than control animals. In general, levels of IDUA expression were slightly higher in peripheral organs for AAVrh10 administered animals although these differences were not significant except for the lung. Levels of IDUA expression between AAV 9 and rh10 were roughly equivalent in the brain. Urinary and tissue GAGs were significantly reduced starting at 3 weeks after vector infusion, with restoration of normal GAG levels by the end of the study in animals treated with either AAV9 or rh10. These results demonstrate that non-invasive intravenous AAV9 or AAVrh10-mediated IDUA gene therapy is a potentially effective treatment for both systemic and CNS manifestations of MPS I, with implications for the treatment of other metabolic and neurological diseases as well.
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spelling pubmed-72428632020-05-26 Intravenous delivery for treatment of mucopolysaccharidosis type I: A comparison of AAV serotypes 9 and rh10 Belur, Lalitha R. Podetz-Pedersen, Kelly M. Tran, Thuy An Mesick, Joshua A. Singh, Nathaniel M. Riedl, Maureen Vulchanova, Lucy Kozarsky, Karen F. McIvor, R. Scott Mol Genet Metab Rep Research Paper Mucopolysaccharidosis type I (MPS I) is an inherited metabolic disorder caused by deficiency of alpha-L-iduronidase (IDUA), resulting in accumulation of heparan and dermatan sulfate glycosaminoglycans (GAGs). Individuals with the most severe form of the disease (Hurler syndrome) suffer from neurodegeneration, intellectual disability, and death by age 10. Current treatments for this disease include allogeneic hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT). However, these treatments do not address CNS manifestations of the disease. In this study we compared the ability of intravenously administered AAV serotypes 9 and rh10 (AAV9 and AAVrh10) for delivery and expression of the IDUA gene in the CNS. Adult C57BL/6 MPS I mice were infused intravenously with either AAV9 or AAVrh10 vector encoding the human IDUA gene. Treated animals demonstrated supraphysiological levels and widespread restoration of IDUA enzyme activity in the plasma and all organs including the CNS. High levels of IDUA enzyme activity were observed in the plasma, brain and spinal cord ranging from 10 to 100-fold higher than heterozygote controls, while levels in peripheral organs were also high, ranging from 1000 to 10,000-fold higher than control animals. In general, levels of IDUA expression were slightly higher in peripheral organs for AAVrh10 administered animals although these differences were not significant except for the lung. Levels of IDUA expression between AAV 9 and rh10 were roughly equivalent in the brain. Urinary and tissue GAGs were significantly reduced starting at 3 weeks after vector infusion, with restoration of normal GAG levels by the end of the study in animals treated with either AAV9 or rh10. These results demonstrate that non-invasive intravenous AAV9 or AAVrh10-mediated IDUA gene therapy is a potentially effective treatment for both systemic and CNS manifestations of MPS I, with implications for the treatment of other metabolic and neurological diseases as well. Elsevier 2020-05-20 /pmc/articles/PMC7242863/ /pubmed/32461912 http://dx.doi.org/10.1016/j.ymgmr.2020.100604 Text en © 2020 The Authors http://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
Belur, Lalitha R.
Podetz-Pedersen, Kelly M.
Tran, Thuy An
Mesick, Joshua A.
Singh, Nathaniel M.
Riedl, Maureen
Vulchanova, Lucy
Kozarsky, Karen F.
McIvor, R. Scott
Intravenous delivery for treatment of mucopolysaccharidosis type I: A comparison of AAV serotypes 9 and rh10
title Intravenous delivery for treatment of mucopolysaccharidosis type I: A comparison of AAV serotypes 9 and rh10
title_full Intravenous delivery for treatment of mucopolysaccharidosis type I: A comparison of AAV serotypes 9 and rh10
title_fullStr Intravenous delivery for treatment of mucopolysaccharidosis type I: A comparison of AAV serotypes 9 and rh10
title_full_unstemmed Intravenous delivery for treatment of mucopolysaccharidosis type I: A comparison of AAV serotypes 9 and rh10
title_short Intravenous delivery for treatment of mucopolysaccharidosis type I: A comparison of AAV serotypes 9 and rh10
title_sort intravenous delivery for treatment of mucopolysaccharidosis type i: a comparison of aav serotypes 9 and rh10
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242863/
https://www.ncbi.nlm.nih.gov/pubmed/32461912
http://dx.doi.org/10.1016/j.ymgmr.2020.100604
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