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Therapeutic benefit after intracranial gene therapy delivered during the symptomatic stage in a feline model of Sandhoff disease

Sandhoff disease (SD) is an autosomal recessive lysosomal storage disease caused by defects in the β-subunit of β-N-acetylhexosaminidase (Hex), the enzyme that catabolizes GM2 ganglioside (GM2). Hex deficiency causes neuronal storage of GM2 and related glycoconjugates, resulting in progressive neuro...

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Autores principales: McCurdy, Victoria J., Johnson, Aime K., Gray-Edwards, Heather L., Randle, Ashley N., Bradbury, Allison M., Morrison, Nancy E., Hwang, Misako, Baker, Henry J., Cox, Nancy R., Sena-Esteves, Miguel, Martin, Douglas R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925702/
https://www.ncbi.nlm.nih.gov/pubmed/32884151
http://dx.doi.org/10.1038/s41434-020-00190-1
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author McCurdy, Victoria J.
Johnson, Aime K.
Gray-Edwards, Heather L.
Randle, Ashley N.
Bradbury, Allison M.
Morrison, Nancy E.
Hwang, Misako
Baker, Henry J.
Cox, Nancy R.
Sena-Esteves, Miguel
Martin, Douglas R.
author_facet McCurdy, Victoria J.
Johnson, Aime K.
Gray-Edwards, Heather L.
Randle, Ashley N.
Bradbury, Allison M.
Morrison, Nancy E.
Hwang, Misako
Baker, Henry J.
Cox, Nancy R.
Sena-Esteves, Miguel
Martin, Douglas R.
author_sort McCurdy, Victoria J.
collection PubMed
description Sandhoff disease (SD) is an autosomal recessive lysosomal storage disease caused by defects in the β-subunit of β-N-acetylhexosaminidase (Hex), the enzyme that catabolizes GM2 ganglioside (GM2). Hex deficiency causes neuronal storage of GM2 and related glycoconjugates, resulting in progressive neurodegeneration and death, typically in infancy. No effective treatment exists for human patients. Adeno-associated virus (AAV) gene therapy led to improved clinical outcome and survival of SD cats treated before the onset of disease symptoms. Most human patients are diagnosed after clinical disease onset, so it is imperative to test AAV gene therapy in symptomatic SD cats to provide a realistic indication of therapeutic benefits that can be expected in humans. In this study, AAVrh8 vectors injected into the thalamus and deep cerebellar nuclei of symptomatic SD cats resulted in widespread central nervous system enzyme distribution, although a substantial burden of storage material remained. Cats treated in the early symptomatic phase showed delayed disease progression and a significant survival increase versus untreated cats. Treatment was less effective when administered later in the disease course, although therapeutic benefit was still possible. Results are encouraging for the treatment of human patients and provide support for the development AAV gene therapy for human SD.
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spelling pubmed-79257022021-05-03 Therapeutic benefit after intracranial gene therapy delivered during the symptomatic stage in a feline model of Sandhoff disease McCurdy, Victoria J. Johnson, Aime K. Gray-Edwards, Heather L. Randle, Ashley N. Bradbury, Allison M. Morrison, Nancy E. Hwang, Misako Baker, Henry J. Cox, Nancy R. Sena-Esteves, Miguel Martin, Douglas R. Gene Ther Article Sandhoff disease (SD) is an autosomal recessive lysosomal storage disease caused by defects in the β-subunit of β-N-acetylhexosaminidase (Hex), the enzyme that catabolizes GM2 ganglioside (GM2). Hex deficiency causes neuronal storage of GM2 and related glycoconjugates, resulting in progressive neurodegeneration and death, typically in infancy. No effective treatment exists for human patients. Adeno-associated virus (AAV) gene therapy led to improved clinical outcome and survival of SD cats treated before the onset of disease symptoms. Most human patients are diagnosed after clinical disease onset, so it is imperative to test AAV gene therapy in symptomatic SD cats to provide a realistic indication of therapeutic benefits that can be expected in humans. In this study, AAVrh8 vectors injected into the thalamus and deep cerebellar nuclei of symptomatic SD cats resulted in widespread central nervous system enzyme distribution, although a substantial burden of storage material remained. Cats treated in the early symptomatic phase showed delayed disease progression and a significant survival increase versus untreated cats. Treatment was less effective when administered later in the disease course, although therapeutic benefit was still possible. Results are encouraging for the treatment of human patients and provide support for the development AAV gene therapy for human SD. 2020-09-03 2021-04 /pmc/articles/PMC7925702/ /pubmed/32884151 http://dx.doi.org/10.1038/s41434-020-00190-1 Text en http://www.nature.com/authors/editorial_policies/license.html#termsUsers may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
McCurdy, Victoria J.
Johnson, Aime K.
Gray-Edwards, Heather L.
Randle, Ashley N.
Bradbury, Allison M.
Morrison, Nancy E.
Hwang, Misako
Baker, Henry J.
Cox, Nancy R.
Sena-Esteves, Miguel
Martin, Douglas R.
Therapeutic benefit after intracranial gene therapy delivered during the symptomatic stage in a feline model of Sandhoff disease
title Therapeutic benefit after intracranial gene therapy delivered during the symptomatic stage in a feline model of Sandhoff disease
title_full Therapeutic benefit after intracranial gene therapy delivered during the symptomatic stage in a feline model of Sandhoff disease
title_fullStr Therapeutic benefit after intracranial gene therapy delivered during the symptomatic stage in a feline model of Sandhoff disease
title_full_unstemmed Therapeutic benefit after intracranial gene therapy delivered during the symptomatic stage in a feline model of Sandhoff disease
title_short Therapeutic benefit after intracranial gene therapy delivered during the symptomatic stage in a feline model of Sandhoff disease
title_sort therapeutic benefit after intracranial gene therapy delivered during the symptomatic stage in a feline model of sandhoff disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925702/
https://www.ncbi.nlm.nih.gov/pubmed/32884151
http://dx.doi.org/10.1038/s41434-020-00190-1
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