Treatment of adult metachromatic leukodystrophy model mice using intrathecal administration of type 9 AAV vector encoding arylsulfatase A

• Published in: Scientific reports Vol. 11; no. 1; p. 20513
• Main Authors: Miyake, Noriko, Miyake, Koichi, Sakai, Atsushi, Yamamoto, Motoko, Suzuki, Hidenori, Shimada, Takashi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.10.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 692/308/2778; 692/308/3187; 692/4017; Age Factors; Animal models; Animals; Arylsulfatase; Brain; Central nervous system; Cerebellum; Cerebellum - metabolism; Cerebroside-sulfatase; Cerebroside-Sulfatase - genetics; Cerebroside-Sulfatase - metabolism; Demyelination; Dependovirus; Disease; Disease Models, Animal; Enzymes; Gene therapy; Genetic disorders; Genetic Therapy - methods; Genetic Vectors; Genomes; Humanities and Social Sciences; Injections, Spinal; Leukodystrophy; Leukodystrophy, Metachromatic - therapy; Lysosomal storage diseases; Mice; Mice, Knockout; multidisciplinary; Neurological disorders; Neurophysiology; Olfactory bulb; Proteins; Science; Science (multidisciplinary); Spinal cord; Spinal Cord - metabolism; Stem cells; Sulfatide; Sulfoglycosphingolipids - metabolism; Vectors (Biology)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-99979-2

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.