Safety of Direct Intraparenchymal AAVrh.10-Mediated Central Nervous System Gene Therapy for Metachromatic Leukodystrophy

Rosenberg, Jonathan B.; Chen, Alvin; De, Bishnu P.; Dyke, Jonathan P.; Ballon, Douglas; Monette, Sébastien; Arbona, Rodolfo J Ricart; Kaminsky, Stephen M.; Crystal, Ronald G.; Sondhi, Dolan

doi:10.1089/hum.2020.269

Cited by 30 publications

(15 citation statements)

References 60 publications

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“…Interestingly, when AAVrh10.hARSA or AAVrh10.Null vector was administered to NHPs via intraparenchymal injection, axonal degeneration was observed in the spinal cord in both groups of animals. 14 The AAVrh10.Null vector used in that study had a functional CAG promoter (same promoter as used with AAV9.hCLN2, referred to as CB7), but no translatable protein product; therefore, it will produce a high level of mRNA but no protein. This is different than the AAV9.Null vector used in our study, which lacked a functional promoter and does not produce mRNA or protein.…”

Section: Discussionmentioning

confidence: 99%

Characterization of AAV-mediated dorsal root ganglionopathy

Buss

Lanigan²,

Zeller³

et al. 2022

Molecular Therapy - Methods & Clinical Development

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Section: Discussionmentioning

confidence: 99%

Characterization of AAV-mediated dorsal root ganglionopathy

Buss

Lanigan²,

Zeller³

et al. 2022

Molecular Therapy - Methods & Clinical Development

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“…Use of one of those strategies may be an effective option for transduction of oligodendrocytes. Recently, Rosenberg et al reported that delivery of ASA through the cerebral spinal fluid is instrumental for ensuring widespread diffusion of the enzyme into the CNS 36 . Although we did not analyze ASA levels in the cerebral spinal fluid, this appears to be an important aspect of intrathecal injection.…”

Section: Discussionmentioning

confidence: 99%

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

Miyake

Sakai

et al. 2021

Sci Rep

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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.

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“…For further purification, the produced AAV particle is isolated using ultracentrifugation and/or ion exchange chromatography. In addition to no severe adverse events, the biosafety of AAV has also been extensively studied in many non-human primate models [ 27 ].…”

Section: Treatment Strategiesmentioning

confidence: 99%

Mammalian Sulfatases: Biochemistry, Disease Manifestation, and Therapy

Mashima

Nakanishi²

2022

IJMS

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Sulfatases are enzymes that catalyze the removal of sulfate from biological substances, an essential process for the homeostasis of the body. They are commonly activated by the unusual amino acid formylglycine, which is formed from cysteine at the catalytic center, mediated by a formylglycine-generating enzyme as a post-translational modification. Sulfatases are expressed in various cellular compartments such as the lysosome, the endoplasmic reticulum, and the Golgi apparatus. The substrates of mammalian sulfatases are sulfolipids, glycosaminoglycans, and steroid hormones. These enzymes maintain neuronal function in both the central and the peripheral nervous system, chondrogenesis and cartilage in the connective tissue, detoxification from xenobiotics and pharmacological compounds in the liver, steroid hormone inactivation in the placenta, and the proper regulation of skin humidification. Human sulfatases comprise 17 genes, 10 of which are involved in congenital disorders, including lysosomal storage disorders, while the function of the remaining seven is still unclear. As for the genes responsible for pathogenesis, therapeutic strategies have been developed. Enzyme replacement therapy with recombinant enzyme agents and gene therapy with therapeutic transgenes delivered by viral vectors are administered to patients. In this review, the biochemical substrates, disease manifestation, and therapy for sulfatases are summarized.

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Safety of Direct Intraparenchymal AAVrh.10-Mediated Central Nervous System Gene Therapy for Metachromatic Leukodystrophy

Cited by 30 publications

References 60 publications

Characterization of AAV-mediated dorsal root ganglionopathy

Characterization of AAV-mediated dorsal root ganglionopathy

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

Mammalian Sulfatases: Biochemistry, Disease Manifestation, and Therapy

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