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Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation

Aspartylglucosaminuria (AGU) is an autosomal recessive lysosomal storage disease caused by loss of the enzyme aspartylglucosaminidase (AGA), resulting in AGA substrate accumulation. AGU patients have a slow but progressive neurodegenerative disease course, for which there is no approved disease-modi...

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Autores principales: Chen, Xin, Snanoudj-Verber, Sarah, Pollard, Laura, Hu, Yuhui, Cathey, Sara S., Tikkanen, Ritva, Gray, Steven J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934581/
https://www.ncbi.nlm.nih.gov/pubmed/33186692
http://dx.doi.org/10.1016/j.ymthe.2020.11.012
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author Chen, Xin
Snanoudj-Verber, Sarah
Pollard, Laura
Hu, Yuhui
Cathey, Sara S.
Tikkanen, Ritva
Gray, Steven J.
author_facet Chen, Xin
Snanoudj-Verber, Sarah
Pollard, Laura
Hu, Yuhui
Cathey, Sara S.
Tikkanen, Ritva
Gray, Steven J.
author_sort Chen, Xin
collection PubMed
description Aspartylglucosaminuria (AGU) is an autosomal recessive lysosomal storage disease caused by loss of the enzyme aspartylglucosaminidase (AGA), resulting in AGA substrate accumulation. AGU patients have a slow but progressive neurodegenerative disease course, for which there is no approved disease-modifying treatment. In this study, AAV9/AGA was administered to Aga(−/−) mice intravenously (i.v.) or intrathecally (i.t.), at a range of doses, either before or after disease pathology begins. At either treatment age, AAV9/AGA administration led to (1) dose dependently increased and sustained AGA activity in body fluids and tissues; (2) rapid, sustained, and dose-dependent elimination of AGA substrate in body fluids; (3) significantly rescued locomotor activity; (4) dose-dependent preservation of Purkinje neurons in the cerebellum; and (5) significantly reduced gliosis in the brain. Treated mice had no abnormal neurological phenotype and maintained body weight throughout the whole experiment to 18 months old. In summary, these results demonstrate that treatment of Aga(−/−) mice with AAV9/AGA is effective and safe, providing strong evidence that AAV9/AGA gene therapy should be considered for human translation. Further, we provide a direct comparison of the efficacy of an i.v. versus i.t. approach using AAV9, which should greatly inform the development of similar treatments for other related lysosomal storage diseases.
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spelling pubmed-79345812022-03-03 Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation Chen, Xin Snanoudj-Verber, Sarah Pollard, Laura Hu, Yuhui Cathey, Sara S. Tikkanen, Ritva Gray, Steven J. Mol Ther Original Article Aspartylglucosaminuria (AGU) is an autosomal recessive lysosomal storage disease caused by loss of the enzyme aspartylglucosaminidase (AGA), resulting in AGA substrate accumulation. AGU patients have a slow but progressive neurodegenerative disease course, for which there is no approved disease-modifying treatment. In this study, AAV9/AGA was administered to Aga(−/−) mice intravenously (i.v.) or intrathecally (i.t.), at a range of doses, either before or after disease pathology begins. At either treatment age, AAV9/AGA administration led to (1) dose dependently increased and sustained AGA activity in body fluids and tissues; (2) rapid, sustained, and dose-dependent elimination of AGA substrate in body fluids; (3) significantly rescued locomotor activity; (4) dose-dependent preservation of Purkinje neurons in the cerebellum; and (5) significantly reduced gliosis in the brain. Treated mice had no abnormal neurological phenotype and maintained body weight throughout the whole experiment to 18 months old. In summary, these results demonstrate that treatment of Aga(−/−) mice with AAV9/AGA is effective and safe, providing strong evidence that AAV9/AGA gene therapy should be considered for human translation. Further, we provide a direct comparison of the efficacy of an i.v. versus i.t. approach using AAV9, which should greatly inform the development of similar treatments for other related lysosomal storage diseases. American Society of Gene & Cell Therapy 2021-03-03 2020-11-11 /pmc/articles/PMC7934581/ /pubmed/33186692 http://dx.doi.org/10.1016/j.ymthe.2020.11.012 Text en 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 Original Article
Chen, Xin
Snanoudj-Verber, Sarah
Pollard, Laura
Hu, Yuhui
Cathey, Sara S.
Tikkanen, Ritva
Gray, Steven J.
Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation
title Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation
title_full Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation
title_fullStr Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation
title_full_unstemmed Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation
title_short Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation
title_sort pre-clinical gene therapy with aav9/aga in aspartylglucosaminuria mice provides evidence for clinical translation
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934581/
https://www.ncbi.nlm.nih.gov/pubmed/33186692
http://dx.doi.org/10.1016/j.ymthe.2020.11.012
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