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.

Multiple Administration of Dexamethasone Possesses a Deferred Long-Term Effect to Glycosylated Components of Mouse Brain

“…The study of carbohydrate chains is a complex task and requires the use of time-consuming methods, for example, mass-spectrometry. An alternative is to use semi-quantitative methods using specific dyes, such as Alcian blue [ 28 ]. Alcian blue, depending on the pH of the dye solution, reveals highly sulfated (pH = 1) or total (pH = 2.5) GAGs.…”

Safety and Efficacy of Intravenous and Intrathecal Delivery of AAV9-Mediated ARSA in Minipigs

“…When administered intravenously, AAV9 can cross the BBB and enter the CNS [52]. The effectiveness of the intravenous administration of rAAV9 was shown in a mouse model [53], and the effectiveness of the intrathecal administration of AAV9-ARSA was shown in 6-week-old mice; however, no improvement in motor behavior was observed in 1-year-old mice [54]. In our study, the intravenous and intrathecal administration of recombinant AAV9 containing a unique codon-optimized sequence of the human ARSA gene were compared and analyzed for their efficacy and safety in minipigs.…”

Preclinical studies in Krabbe disease: A model for the investigation of novel combination therapies for lysosomal storage diseases

“…There is evidence of a similar decline in AAV episome copy number and therapeutic efficacy over time for other AAV-treated LSDs. 179 , 180 , 181 , 182 , 183 There are still many unanswered questions regarding this proposed pathway, including determining the timing and specific mechanisms of each step. Furthermore, a more complete understanding of the relationship between the dose of AAV and the duration of protection against disease in the human brain is needed.…”