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Therapeutic benefit after intracranial gene therapy delivered during the symptomatic stage in a feline model of Sandhoff disease

Gene Therapy volume 28, pages 142–154 (2021)Cite this article

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Abstract

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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Fig. 1: Survival and clinical progression of postsymptomatic AAV-treated SD cats and untreated SD cats.
Fig. 2: Neurological exam performance of postsymptomatic AAV-treated SD cats versus untreated SD cats.
Fig. 3: MRI evaluation of late postsymptomatic AAV-treated SD cats and untreated controls.
Fig. 4: Therapeutic enzyme distribution in the CNS of postsymptomatic AAV-treated SD cats.
Fig. 5: Storage in the CNS of postsymptomatic AAV-treated SD cats.
Fig. 6: Normalization of lysosomal mannosidase activity in the CNS and liver of postsymptomatic AAV-treated SD cats.

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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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Acknowledgements

All contributors have been acknowledged by authorship.

Funding

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.

Author information

Author notes

  1. Victoria J. McCurdy

    Present address: Department of Biological Sciences, Mississippi State University, Mississippi State, MA, USA

  2. Allison M. Bradbury

    Present address: Center for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH, USA

  3. Allison M. Bradbury

    Present address: Department of Pediatrics, The Ohio State University Wexner Medical Center, Columbus, OH, USA

Authors and Affiliations

  1. Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA

    Victoria J. McCurdy, Heather L. Gray-Edwards, Ashley N. Randle, Allison M. Bradbury, Nancy E. Morrison, Misako Hwang, Henry J. Baker, Nancy R. Cox & Douglas R. Martin

  2. Department of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA

    Victoria J. McCurdy, Allison M. Bradbury & Douglas R. Martin

  3. Department of Clinical Sciences, Auburn College of Veterinary Medicine, Auburn University, Auburn, AL, USA

    Aime K. Johnson

  4. Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA

    Henry J. Baker & Nancy R. Cox

  5. Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA

    Miguel Sena-Esteves

  6. Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA

    Miguel Sena-Esteves

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Correspondence to Douglas R. Martin.

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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).

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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

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