Sandhoff disease (SD) is an autosomal recessive lysosomal storage disease caused by defects in the β-subunit of β-N-acetylhexosaminidase (Hex), the enzyme that catabolizes GM2 ganglioside. Hex deficiency causes neuronal storage of GM2 and related glycoconjugates, resulting in progressive neurodegeneration and death, typically in infancy. No effective treatment exists for human patients. Adeno-associated virus (AAV) gene therapy led to improved clinical outcome and survival of SD cats treated before the onset of disease symptoms. Most human patients are diagnosed after clinical disease onset, so it is imperative to test AAV-gene therapy in symptomatic SD cats to provide a realistic indication of therapeutic benefits that can be expected in humans. In this study, AAVrh8 vectors injected into the thalamus and deep cerebellar nuclei of symptomatic SD cats resulted in widespread central nervous system enzyme distribution, although a substantial burden of storage material remained. Cats treated in the early symptomatic phase showed delayed disease progression and a significant survival increase versus untreated cats. Treatment was less effective when administered later in the disease course, although therapeutic benefit was still possible. Results are encouraging for the treatment of human patients and provide support for the development AAV-gene therapy for human SD.
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The SAS 9.2 software codes used to generate survival curves, logrank test survival statistics, and Wilcoxon signed rank statistics can be provided upon request by contacting the corresponding author.
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All contributors have been acknowledged by authorship.
This work was funded by a grant from the US National Institutes of Health (U01NS064096 to MS-E and DRM) and contributions from the Scott-Ritchey Research Center, National Tay-Sachs and Allied Diseases Association, the Jewish Community Endowment Fund, and the Cure Tay-Sachs Foundation.
Conflict of interest
The authors are beneficiaries of a licensing agreement with Axovant Gene Therapies (New York City) based partly on this technology. MS-E and DRM are shareholders in Lysogene (Neuilly-sur-Seine, France).
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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McCurdy, V.J., Johnson, A.K., Gray-Edwards, H.L. et al. Therapeutic benefit after intracranial gene therapy delivered during the symptomatic stage in a feline model of Sandhoff disease. Gene Ther 28, 142–154 (2021). https://doi.org/10.1038/s41434-020-00190-1