Abstract

GM1 gangliosidosis is a fatal neurodegenerative affliction caused by a deficiency of lysosomal β-galactosidase. In its most severe grade, GM1 gangliosidosis causes death by 4 years of age, and no effective treatments be. Previous work has shown that injection of the brain parenchyma with an adeno-associated viral (AAV) vector provides pronounced therapeutic benefit in a feline GM1 model. To develop a less invasive treatment for the encephalon and increase systemic biodistribution, intravenous injection of AAV9 was evaluated.

AAV9 expressing feline β-galactosidase was intravenously administered at 1.5×1013 vector genomes/kg torso weight to vi GM1 cats at ∼1 month of age. The animals were divided into two cohorts: (i) a long-term group, which was followed to humane cease point; and (2) a brusk-term grouping, which was analysed 16 weeks post-treatment. Clinical assessments included neurological exams, CSF and urine biomarkers, and 7 T MRI and magentic resonance spectroscopy (MRS). Post-mortem analysis included β-galactosidase and virus distribution, histological analysis and ganglioside content.

Untreated GM1 animals survived viii.0 ± 0.6 months while intravenous treatment increased survival to an average of three.five years (n = 2) with substantial improvements in quality of life and neurological function. Neurological abnormalities, which in untreated animals progress to the inability to stand and debilitating neurological disease by 8 months of age, were mild in all treated animals. CSF biomarkers were normalized, indicating decreased CNS cell harm in the treated animals. Urinary glycosaminoglycans decreased to normal levels in the long-term accomplice. MRI and MRS showed partial preservation of the encephalon in treated animals, which was supported by post-mortem histological evaluation. β-Galactosidase activity was increased throughout the CNS, reaching carrier levels in much of the cerebrum and normal levels in the cerebellum, spinal cord and CSF. Ganglioside accumulation was significantly reduced past handling. Peripheral tissues such as middle, skeletal muscle, and sciatic nerve also had normal β-galactosidase activity in treated GM1 cats. GM1 histopathology was largely corrected with treatment. At that place was no evidence of tumorigenesis or toxicity.

Restoration of β-galactosidase activity in the CNS and peripheral organs by intravenous factor therapy led to profound increases in lifespan and quality of life in GM1 cats. These data support the hope of intravenous gene therapy as a safe, constructive treatment for GM1 gangliosidosis.

© The Writer(s) (2021). Published past Oxford Academy Press on behalf of the Guarantors of Encephalon. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

© The Writer(s) (2021). Published past Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, delight email: journals.permissions@oup.com

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