AAV-mediated gene delivery in a feline model of Sandhoff disease corrects lysosomal storage in the central nervous system

ASN Neuro. 2015 Apr 13;7(2):1759091415569908. doi: 10.1177/1759091415569908. Print 2015 Mar-Apr.


Sandhoff disease (SD) is an autosomal recessive neurodegenerative disease caused by a mutation in the gene for the β-subunit of β-N-acetylhexosaminidase (Hex), resulting in the inability to catabolize ganglioside GM2 within the lysosomes. SD presents with an accumulation of GM2 and its asialo derivative GA2, primarily in the central nervous system. Myelin-enriched glycolipids, cerebrosides and sulfatides, are also decreased in SD corresponding with dysmyelination. At present, no treatment exists for SD. Previous studies have shown the therapeutic benefit of adeno-associated virus (AAV) vector-mediated gene therapy in the treatment of SD in murine and feline models. In this study, we treated presymptomatic SD cats with AAVrh8 vectors expressing feline Hex in the thalamus combined with intracerebroventricular (Thal/ICV) injections. Treated animals showed clearly improved neurologic function and quality of life, manifested in part by prevention or attenuation of whole-body tremors characteristic of untreated animals. Hex activity was significantly elevated, whereas storage of GM2 and GA2 was significantly decreased in tissue samples taken from the cortex, cerebellum, thalamus, and cervical spinal cord. Treatment also increased levels of myelin-enriched cerebrosides and sulfatides in the cortex and thalamus. This study demonstrates the therapeutic potential of AAV for feline SD and suggests a similar potential for human SD patients.

Keywords: Sandhoff disease; adeno-associated virus; ganglioside; gene therapy; β-hexosaminidase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / pathology
  • Brain / physiopathology
  • Cats
  • Central Nervous System / metabolism
  • Cerebrosides / metabolism
  • Dependovirus / genetics*
  • Disease Models, Animal
  • Disease Progression
  • G(M2) Ganglioside / metabolism
  • Gangliosides / metabolism
  • Genetic Therapy / methods*
  • Genetic Vectors
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Lysosomes / metabolism*
  • Quality of Life
  • Sandhoff Disease / pathology
  • Sandhoff Disease / physiopathology
  • Sandhoff Disease / psychology
  • Sandhoff Disease / therapy*
  • Severity of Illness Index
  • Spinal Cord / pathology
  • Spinal Cord / physiopathology
  • Sulfoglycosphingolipids / metabolism
  • Treatment Outcome


  • Cerebrosides
  • Gangliosides
  • Homeodomain Proteins
  • Sulfoglycosphingolipids
  • G(M2) Ganglioside
  • ganglio-N-triaosylceramide