Treatment of adult metachromatic leukodystrophy model mice using intrathecal administration of type 9 AAV vector encoding arylsulfatase A
Abstract Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by an arylsulfatase A (ARSA) deficiency and characterized by severe neurological symptoms resulting from demyelination within the central and peripheral nervous systems. We investigated the feasibility and efficacy of...
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| Format: | Article |
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Nature Portfolio
2021-10-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-99979-2 |
| _version_ | 1831788315386314752 |
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| author | Noriko Miyake Koichi Miyake Atsushi Sakai Motoko Yamamoto Hidenori Suzuki Takashi Shimada |
| author_facet | Noriko Miyake Koichi Miyake Atsushi Sakai Motoko Yamamoto Hidenori Suzuki Takashi Shimada |
| author_sort | Noriko Miyake |
| collection | DOAJ |
| description | Abstract Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by an arylsulfatase A (ARSA) deficiency and characterized by severe neurological symptoms resulting from demyelination within the central and peripheral nervous systems. We investigated the feasibility and efficacy of intrathecal administration of a type 9 adeno-associated viral vector encoding ARSA (AAV9/ARSA) for the treatment of 6-week-old MLD model mice, which are presymptomatic, and 1-year-old mice, which exhibit neurological abnormalities. Immunohistochemical analysis following AAV9/ARSA administration showed ARSA expression within the brain, with highest activities in the cerebellum and olfactory bulbs. In mice treated at 1 year, alcian blue staining and quantitative analysis revealed significant decreases in stored sulfatide. Behaviorally, mice treated at 1 year showed no improvement in their ability to traverse narrow balance beams as compared to untreated mice. By contrast, MLD mice treated at 6 weeks showed significant decreases in stored sulfatide throughout the entire brain and improved ability to traverse narrow balance beams. These findings suggest intrathecal administration of an AAV9/ARSA vector is a promising approach to treating genetic diseases of the central nervous system, including MLD, though it may be essential to begin therapy before the onset of neurological symptoms. |
| first_indexed | 2024-12-22T13:47:05Z |
| format | Article |
| id | doaj.art-4dd8f9e3c6f542a4b4d9938ecef5e221 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-22T13:47:05Z |
| publishDate | 2021-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-4dd8f9e3c6f542a4b4d9938ecef5e2212022-12-21T18:23:46ZengNature PortfolioScientific Reports2045-23222021-10-0111111210.1038/s41598-021-99979-2Treatment of adult metachromatic leukodystrophy model mice using intrathecal administration of type 9 AAV vector encoding arylsulfatase ANoriko Miyake0Koichi Miyake1Atsushi Sakai2Motoko Yamamoto3Hidenori Suzuki4Takashi Shimada5Department of Biochemistry and Molecular Biology, Nippon Medical SchoolDepartment of Gene Therapy, Nippon Medical SchoolDepartment of Pharmacology, Nippon Medical SchoolDepartment of Biochemistry and Molecular Biology, Nippon Medical SchoolDepartment of Pharmacology, Nippon Medical SchoolDepartment of Biochemistry and Molecular Biology, Nippon Medical SchoolAbstract Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by an arylsulfatase A (ARSA) deficiency and characterized by severe neurological symptoms resulting from demyelination within the central and peripheral nervous systems. We investigated the feasibility and efficacy of intrathecal administration of a type 9 adeno-associated viral vector encoding ARSA (AAV9/ARSA) for the treatment of 6-week-old MLD model mice, which are presymptomatic, and 1-year-old mice, which exhibit neurological abnormalities. Immunohistochemical analysis following AAV9/ARSA administration showed ARSA expression within the brain, with highest activities in the cerebellum and olfactory bulbs. In mice treated at 1 year, alcian blue staining and quantitative analysis revealed significant decreases in stored sulfatide. Behaviorally, mice treated at 1 year showed no improvement in their ability to traverse narrow balance beams as compared to untreated mice. By contrast, MLD mice treated at 6 weeks showed significant decreases in stored sulfatide throughout the entire brain and improved ability to traverse narrow balance beams. These findings suggest intrathecal administration of an AAV9/ARSA vector is a promising approach to treating genetic diseases of the central nervous system, including MLD, though it may be essential to begin therapy before the onset of neurological symptoms.https://doi.org/10.1038/s41598-021-99979-2 |
| spellingShingle | Noriko Miyake Koichi Miyake Atsushi Sakai Motoko Yamamoto Hidenori Suzuki Takashi Shimada Treatment of adult metachromatic leukodystrophy model mice using intrathecal administration of type 9 AAV vector encoding arylsulfatase A Scientific Reports |
| title | Treatment of adult metachromatic leukodystrophy model mice using intrathecal administration of type 9 AAV vector encoding arylsulfatase A |
| title_full | Treatment of adult metachromatic leukodystrophy model mice using intrathecal administration of type 9 AAV vector encoding arylsulfatase A |
| title_fullStr | Treatment of adult metachromatic leukodystrophy model mice using intrathecal administration of type 9 AAV vector encoding arylsulfatase A |
| title_full_unstemmed | Treatment of adult metachromatic leukodystrophy model mice using intrathecal administration of type 9 AAV vector encoding arylsulfatase A |
| title_short | Treatment of adult metachromatic leukodystrophy model mice using intrathecal administration of type 9 AAV vector encoding arylsulfatase A |
| title_sort | treatment of adult metachromatic leukodystrophy model mice using intrathecal administration of type 9 aav vector encoding arylsulfatase a |
| url | https://doi.org/10.1038/s41598-021-99979-2 |
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