Adeno-Associated Virus Gene Therapy in a Sheep Model of Tay-Sachs Disease

Hum Gene Ther. 2018 Mar;29(3):312-326. doi: 10.1089/hum.2017.163. Epub 2017 Sep 18.


Tay-Sachs disease (TSD) is a fatal neurodegenerative disorder caused by a deficiency of the enzyme hexosaminidase A (HexA). TSD also occurs in sheep, the only experimental model of TSD that has clinical signs of disease. The natural history of sheep TSD was characterized using serial neurological evaluations, 7 Tesla magnetic resonance imaging, echocardiograms, electrodiagnostics, and cerebrospinal fluid biomarkers. Intracranial gene therapy was also tested using AAVrh8 monocistronic vectors encoding the α-subunit of Hex (TSD α) or a mixture of two vectors encoding both the α and β subunits separately (TSD α + β) injected at high (1.3 × 1013 vector genomes) or low (4.2 × 1012 vector genomes) dose. Delay of symptom onset and/or reduction of acquired symptoms were noted in all adeno-associated virus-treated sheep. Postmortem evaluation showed superior HexA and vector genome distribution in the brain of TSD α + β sheep compared to TSD α sheep, but spinal cord distribution was low in all groups. Isozyme analysis showed superior HexA formation after treatment with both vectors (TSD α + β), and ganglioside clearance was most widespread in the TSD α + β high-dose sheep. Microglial activation and proliferation in TSD sheep-most prominent in the cerebrum-were attenuated after gene therapy. This report demonstrates therapeutic efficacy for TSD in the sheep brain, which is on the same order of magnitude as a child's brain.

Keywords: Tay-Sachs; adeno-associated virus; animal model; gangliosidosis; gene therapy; sheep.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / diagnostic imaging
  • Brain / enzymology
  • Dependovirus*
  • Disease Models, Animal
  • Echocardiography
  • Genetic Therapy*
  • Humans
  • Magnetic Resonance Imaging
  • Microglia / enzymology
  • Sheep
  • Tay-Sachs Disease / diagnostic imaging
  • Tay-Sachs Disease / enzymology
  • Tay-Sachs Disease / genetics
  • Tay-Sachs Disease / therapy*
  • beta-Hexosaminidase alpha Chain / biosynthesis*
  • beta-Hexosaminidase alpha Chain / genetics
  • beta-Hexosaminidase beta Chain / biosynthesis*
  • beta-Hexosaminidase beta Chain / genetics


  • beta-Hexosaminidase alpha Chain
  • beta-Hexosaminidase beta Chain