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A novel gene editing system to treat both Tay-Sachs and Sandhoff diseases

The GM2-gangliosidoses are neurological diseases causing premature death, thus developing effective treatment protocols is urgent. GM2-gangliosidoses result from deficiency of a lysosomal enzyme β-hexosaminidase (Hex) and subsequent accumulation of GM2 gangliosides. Genetic changes in HEXA, encoding...

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Autores principales: Ou, Li, Przybilla, Michael J, Tăbăran, Alexandru-Flaviu, Overn, Paula, O’Sullivan, M. Gerard, Jiang, Xuntian, Sidhu, Rohini, Kell, Pamela J., Ory, Daniel S., Whitley, Chester B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260097/
https://www.ncbi.nlm.nih.gov/pubmed/31896760
http://dx.doi.org/10.1038/s41434-019-0120-5
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author Ou, Li
Przybilla, Michael J
Tăbăran, Alexandru-Flaviu
Overn, Paula
O’Sullivan, M. Gerard
Jiang, Xuntian
Sidhu, Rohini
Kell, Pamela J.
Ory, Daniel S.
Whitley, Chester B.
author_facet Ou, Li
Przybilla, Michael J
Tăbăran, Alexandru-Flaviu
Overn, Paula
O’Sullivan, M. Gerard
Jiang, Xuntian
Sidhu, Rohini
Kell, Pamela J.
Ory, Daniel S.
Whitley, Chester B.
author_sort Ou, Li
collection PubMed
description The GM2-gangliosidoses are neurological diseases causing premature death, thus developing effective treatment protocols is urgent. GM2-gangliosidoses result from deficiency of a lysosomal enzyme β-hexosaminidase (Hex) and subsequent accumulation of GM2 gangliosides. Genetic changes in HEXA, encoding the Hex α subunit, or HEXB, encoding the Hex β subunit, causes Tay-Sachs disease and Sandhoff disease, respectively. Previous studies have showed that a modified human Hex μ subunit (HEXM) can treat both Tay-Sachs and Sandhoff diseases by forming a homodimer to degrade GM2 gangliosides. To this end, we applied this HEXM subunit in our PS813 gene editing system to treat neonatal Sandhoff mice. Through AAV delivery of the CRISPR system, a promoterless HEXM cDNA will be integrated into the albumin safe harbor locus, and lysosomal enzyme will be expressed and secreted from edited hepatocytes. Four months after the i.v. of AAV vectors, plasma MUGS and MUG activities reached up to 144- and 17-fold of wildtype levels (n=10, p<0.0001), respectively. More importantly, MUGS and MUG activities in the brain also increased significantly compared with untreated Sandhoff mice (p<0.001). Further, HPLC-MS/MS analysis showed that GM2 gangliosides in multiple tissues, except the brain, of treated mice were reduced to normal levels. Rotarod analysis showed that coordination and motor memory of treated mice were improved (p<0.05). Histological analysis of H&E stained tissues showed reduced cellular vacuolation in the brain and liver of treated Sandhoff mice. These results demonstrate the potential of developing a treatment of in vivo genome editing for Tay-Sachs and Sandhoff patients.
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spelling pubmed-72600972020-07-02 A novel gene editing system to treat both Tay-Sachs and Sandhoff diseases Ou, Li Przybilla, Michael J Tăbăran, Alexandru-Flaviu Overn, Paula O’Sullivan, M. Gerard Jiang, Xuntian Sidhu, Rohini Kell, Pamela J. Ory, Daniel S. Whitley, Chester B. Gene Ther Article The GM2-gangliosidoses are neurological diseases causing premature death, thus developing effective treatment protocols is urgent. GM2-gangliosidoses result from deficiency of a lysosomal enzyme β-hexosaminidase (Hex) and subsequent accumulation of GM2 gangliosides. Genetic changes in HEXA, encoding the Hex α subunit, or HEXB, encoding the Hex β subunit, causes Tay-Sachs disease and Sandhoff disease, respectively. Previous studies have showed that a modified human Hex μ subunit (HEXM) can treat both Tay-Sachs and Sandhoff diseases by forming a homodimer to degrade GM2 gangliosides. To this end, we applied this HEXM subunit in our PS813 gene editing system to treat neonatal Sandhoff mice. Through AAV delivery of the CRISPR system, a promoterless HEXM cDNA will be integrated into the albumin safe harbor locus, and lysosomal enzyme will be expressed and secreted from edited hepatocytes. Four months after the i.v. of AAV vectors, plasma MUGS and MUG activities reached up to 144- and 17-fold of wildtype levels (n=10, p<0.0001), respectively. More importantly, MUGS and MUG activities in the brain also increased significantly compared with untreated Sandhoff mice (p<0.001). Further, HPLC-MS/MS analysis showed that GM2 gangliosides in multiple tissues, except the brain, of treated mice were reduced to normal levels. Rotarod analysis showed that coordination and motor memory of treated mice were improved (p<0.05). Histological analysis of H&E stained tissues showed reduced cellular vacuolation in the brain and liver of treated Sandhoff mice. These results demonstrate the potential of developing a treatment of in vivo genome editing for Tay-Sachs and Sandhoff patients. 2020-01-02 2020-05 /pmc/articles/PMC7260097/ /pubmed/31896760 http://dx.doi.org/10.1038/s41434-019-0120-5 Text en Users 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
Ou, Li
Przybilla, Michael J
Tăbăran, Alexandru-Flaviu
Overn, Paula
O’Sullivan, M. Gerard
Jiang, Xuntian
Sidhu, Rohini
Kell, Pamela J.
Ory, Daniel S.
Whitley, Chester B.
A novel gene editing system to treat both Tay-Sachs and Sandhoff diseases
title A novel gene editing system to treat both Tay-Sachs and Sandhoff diseases
title_full A novel gene editing system to treat both Tay-Sachs and Sandhoff diseases
title_fullStr A novel gene editing system to treat both Tay-Sachs and Sandhoff diseases
title_full_unstemmed A novel gene editing system to treat both Tay-Sachs and Sandhoff diseases
title_short A novel gene editing system to treat both Tay-Sachs and Sandhoff diseases
title_sort novel gene editing system to treat both tay-sachs and sandhoff diseases
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260097/
https://www.ncbi.nlm.nih.gov/pubmed/31896760
http://dx.doi.org/10.1038/s41434-019-0120-5
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