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Widespread correction of central nervous system disease after intracranial gene therapy in a feline model of Sandhoff disease

Gene Therapy volume 22, pages 181–189 (2015)Cite this article

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Abstract

Sandhoff disease (SD) is caused by deficiency of N-acetyl-β-hexosaminidase (Hex) resulting in pathological accumulation of GM2 ganglioside in lysosomes of the central nervous system (CNS) and progressive neurodegeneration. Currently, there is no treatment for SD, which often results in death by the age of five years. Adeno-associated virus (AAV) gene therapy achieved global CNS Hex restoration and widespread normalization of storage in the SD mouse model. Using a similar treatment approach, we sought to translate the outcome in mice to the feline SD model as an important step toward human clinical trials. Sixteen weeks after four intracranial injections of AAVrh8 vectors, Hex activity was restored to above normal levels throughout the entire CNS and in cerebrospinal fluid, despite a humoral immune response to the vector. In accordance with significant normalization of a secondary lysosomal biomarker, ganglioside storage was substantially improved, but not completely cleared. At the study endpoint, 5-month-old AAV-treated SD cats had preserved neurological function and gait compared with untreated animals (humane endpoint, 4.4±0.6 months) demonstrating clinical benefit from AAV treatment. Translation of widespread biochemical disease correction from the mouse to the feline SD model provides optimism for treatment of the larger human CNS with minimal modification of approach.

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Acknowledgements

This work was funded by a grant from the US National Institutes of Health (U01NS064096 to MSE 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. The authors declare that they have no conflicts of interest.

Author information

Author notes

  1. V J McCurdy

    Present address: 7Current address: Department of Biological Sciences, Mississippi State University, Mississippi State, MS, USA,

Authors and Affiliations

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

    V J McCurdy, A M Bradbury, A N Randle, M Hwang, H L Gray-Edwards, N E Morrison, H J Baker, N R Cox & D R Martin

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

    V J McCurdy, A M Bradbury, B L Brunson & D R Martin

  3. Biology Department, Boston College, Chestnut Hill, MA, USA

    H E Rockwell, J R Arthur & T N Seyfried

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

    A K Johnson & J A Johnson

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

    H J Baker & N R Cox

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

    M Sena-Esteves

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  1. V J McCurdy
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Correspondence to D R Martin.

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Competing interests

Dr Martin and Dr Sena-Esteves received NIH funding to perform this study. Dr Martin received funding 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 to perform this study. All other authors declare no conflict of interest.

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McCurdy, V., Rockwell, H., Arthur, J. et al. Widespread correction of central nervous system disease after intracranial gene therapy in a feline model of Sandhoff disease. Gene Ther 22, 181–189 (2015). https://doi.org/10.1038/gt.2014.108

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