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 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.

• Authors: Noriko Miyake, Koichi Miyake, Atsushi Sakai, Motoko Yamamoto, Hidenori Suzuki, Takashi Shimada
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 20513 (10 15 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 34654893 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Sulfoglycosphingolipids
• Cerebroside-Sulfatase

Topics

• Age Factors
• Animals
• Cerebellum (metabolism)
• Cerebroside-Sulfatase (genetics, metabolism)
• Dependovirus
• Disease Models, Animal
• Genetic Therapy (methods)
• Genetic Vectors
• Injections, Spinal
• Leukodystrophy, Metachromatic (therapy)
• Mice, Knockout
• Spinal Cord (metabolism)
• Sulfoglycosphingolipids (metabolism)
• Mice