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.
Highlights
Metachromatic leukodystrophy (MLD) is an autosomal recessive inherited lysosomal storage disorder caused by a deficiency in the lysosomal enzyme arylsulfatase A (ARSA), which catalyzes the degradation of galactosyl3-sulfate ceramide, a major myelin s phingolipid[1]
To determine whether overt neurological symptoms could be reversed by the gene therapy, we assessed the effect of AAV9/ARSA in 1-year-old MLD mice, which already exhibited the neurological symptoms of the disease
Because AAV gene therapy for MLD has yet to be tested intrathecally, and human trials have been limited to ex vivo lentiviral-mediated hematopoietic stem cell gene t herapy[12,13] and intracerebral injection of AAV in MLD patients[25], it is important to examine the effect of intrathecal administration of AAV9/ARSA for the treatment of MLD
Summary
Metachromatic leukodystrophy (MLD) is an autosomal recessive inherited lysosomal storage disorder caused by a deficiency in the lysosomal enzyme arylsulfatase A (ARSA), which catalyzes the degradation of galactosyl3-sulfate ceramide (sulfatide), a major myelin s phingolipid[1] This disease is characterized pathologically by myelin degeneration in both the central and peripheral nervous systems (CNS and PNS)[2]. We recently succeeded in treating neonatal ARSA knockout MLD model mice through systemic gene delivery of a single-strand type 9 adeno-associated viral vector encoding human ARSA (AAV9/ARSA)[14]. Because AAV gene therapy for MLD has yet to be tested intrathecally, and human trials have been limited to ex vivo lentiviral-mediated hematopoietic stem cell gene t herapy[12,13] and intracerebral injection of AAV in MLD patients[25], it is important to examine the effect of intrathecal administration of AAV9/ARSA for the treatment of MLD
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