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Non-clinical Safety and Efficacy of an AAV2/8 Vector Administered Intravenously for Treatment of Mucopolysaccharidosis Type VI
In vivo gene therapy with adeno-associated viral (AAV) vectors is safe and effective in humans. We recently demonstrated that AAV8-mediated liver gene transfer is effective in animal models of mucopolysaccharidosis type VI (MPS VI), a rare lysosomal storage disease that is caused by arylsulfatase B ...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552066/ https://www.ncbi.nlm.nih.gov/pubmed/28932756 http://dx.doi.org/10.1016/j.omtm.2017.07.004 |
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author | Ferla, Rita Alliegro, Marialuisa Marteau, Jean-Brice Dell’Anno, Margherita Nusco, Edoardo Pouillot, Severine Galimberti, Stefania Valsecchi, Maria Grazia Zuliani, Vincent Auricchio, Alberto |
author_facet | Ferla, Rita Alliegro, Marialuisa Marteau, Jean-Brice Dell’Anno, Margherita Nusco, Edoardo Pouillot, Severine Galimberti, Stefania Valsecchi, Maria Grazia Zuliani, Vincent Auricchio, Alberto |
author_sort | Ferla, Rita |
collection | PubMed |
description | In vivo gene therapy with adeno-associated viral (AAV) vectors is safe and effective in humans. We recently demonstrated that AAV8-mediated liver gene transfer is effective in animal models of mucopolysaccharidosis type VI (MPS VI), a rare lysosomal storage disease that is caused by arylsulfatase B (ARSB) deficiency. In preparing for a first-in-human trial, we performed non-clinical studies to assess the safety of intravenous administrations of AAV2/8.TBG.hARSB produced under good manufacturing practice-like conditions. No toxicity was observed in AAV-treated mice, except for a transient increase in alanine aminotransferase in females and thyroid epithelial hypertrophy. AAV2/8.TBG.hARSB biodistribution and expression confirmed the liver as the main site of both infection and transduction. Shedding and breeding studies suggest that the risk of both horizontal and germline transmission is minimal. An AAV dose-response study in MPS VI mice was performed to define the range of doses to be used in the clinical study. Overall, these data support the non-clinical safety and efficacy of AAV2/8.TBG.hARSB and pave the way for a phase I/II clinical trial based on intravascular infusions of AAV8 in patients with MPS VI. |
format | Online Article Text |
id | pubmed-5552066 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-55520662017-09-20 Non-clinical Safety and Efficacy of an AAV2/8 Vector Administered Intravenously for Treatment of Mucopolysaccharidosis Type VI Ferla, Rita Alliegro, Marialuisa Marteau, Jean-Brice Dell’Anno, Margherita Nusco, Edoardo Pouillot, Severine Galimberti, Stefania Valsecchi, Maria Grazia Zuliani, Vincent Auricchio, Alberto Mol Ther Methods Clin Dev Original Article In vivo gene therapy with adeno-associated viral (AAV) vectors is safe and effective in humans. We recently demonstrated that AAV8-mediated liver gene transfer is effective in animal models of mucopolysaccharidosis type VI (MPS VI), a rare lysosomal storage disease that is caused by arylsulfatase B (ARSB) deficiency. In preparing for a first-in-human trial, we performed non-clinical studies to assess the safety of intravenous administrations of AAV2/8.TBG.hARSB produced under good manufacturing practice-like conditions. No toxicity was observed in AAV-treated mice, except for a transient increase in alanine aminotransferase in females and thyroid epithelial hypertrophy. AAV2/8.TBG.hARSB biodistribution and expression confirmed the liver as the main site of both infection and transduction. Shedding and breeding studies suggest that the risk of both horizontal and germline transmission is minimal. An AAV dose-response study in MPS VI mice was performed to define the range of doses to be used in the clinical study. Overall, these data support the non-clinical safety and efficacy of AAV2/8.TBG.hARSB and pave the way for a phase I/II clinical trial based on intravascular infusions of AAV8 in patients with MPS VI. American Society of Gene & Cell Therapy 2017-07-24 /pmc/articles/PMC5552066/ /pubmed/28932756 http://dx.doi.org/10.1016/j.omtm.2017.07.004 Text en © 2017 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Original Article Ferla, Rita Alliegro, Marialuisa Marteau, Jean-Brice Dell’Anno, Margherita Nusco, Edoardo Pouillot, Severine Galimberti, Stefania Valsecchi, Maria Grazia Zuliani, Vincent Auricchio, Alberto Non-clinical Safety and Efficacy of an AAV2/8 Vector Administered Intravenously for Treatment of Mucopolysaccharidosis Type VI |
title | Non-clinical Safety and Efficacy of an AAV2/8 Vector Administered Intravenously for Treatment of Mucopolysaccharidosis Type VI |
title_full | Non-clinical Safety and Efficacy of an AAV2/8 Vector Administered Intravenously for Treatment of Mucopolysaccharidosis Type VI |
title_fullStr | Non-clinical Safety and Efficacy of an AAV2/8 Vector Administered Intravenously for Treatment of Mucopolysaccharidosis Type VI |
title_full_unstemmed | Non-clinical Safety and Efficacy of an AAV2/8 Vector Administered Intravenously for Treatment of Mucopolysaccharidosis Type VI |
title_short | Non-clinical Safety and Efficacy of an AAV2/8 Vector Administered Intravenously for Treatment of Mucopolysaccharidosis Type VI |
title_sort | non-clinical safety and efficacy of an aav2/8 vector administered intravenously for treatment of mucopolysaccharidosis type vi |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552066/ https://www.ncbi.nlm.nih.gov/pubmed/28932756 http://dx.doi.org/10.1016/j.omtm.2017.07.004 |
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