Effective gene therapy in an authentic model of Tay-Sachs-related diseases

M Begoña Cachón-González, Susan Z Wang, Andrew Lynch, Robin Ziegler, Seng H Cheng, Timothy M Cox

Research output: Contribution to journalArticlepeer-review

104 Citations (Scopus)


Tay-Sachs disease is a prototypic neurodegenerative disease. Lysosomal storage of GM2 ganglioside in Tay-Sachs and the related disorder, Sandhoff disease, is caused by deficiency of beta-hexosaminidase A, a heterodimeric protein. Tay-Sachs-related diseases (GM2 gangliosidoses) are incurable, but gene therapy has the potential for widespread correction of the underlying lysosomal defect by means of the secretion-recapture cellular pathway for enzymatic complementation. Sandhoff mice, lacking the beta-subunit of hexosaminidase, manifest many signs of classical human Tay-Sachs disease and, with an acute course, die before 20 weeks of age. We treated Sandhoff mice by stereotaxic intracranial inoculation of recombinant adeno-associated viral vectors encoding the complementing human beta-hexosaminidase alpha and beta subunit genes and elements, including an HIV tat sequence, to enhance protein expression and distribution. Animals survived for >1 year with sustained, widespread, and abundant enzyme delivery in the nervous system. Onset of the disease was delayed with preservation of motor function; inflammation and GM2 ganglioside storage in the brain and spinal cord was reduced. Gene delivery of beta-hexosaminidase A by using adeno-associated viral vectors has realistic potential for treating the human Tay-Sachs-related diseases.

Original languageEnglish
Pages (from-to)10373-8
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number27
Publication statusPublished - 5 Jul 2006


  • Animals
  • Body Weight
  • Disease Models, Animal
  • Gene Expression Regulation, Enzymologic
  • Genetic Therapy
  • Genetic Vectors
  • Glycosphingolipids
  • Inflammation
  • Mice
  • Mice, Knockout
  • Microscopy, Electron
  • Protein Subunits
  • Survival Rate
  • Tay-Sachs Disease
  • beta-N-Acetylhexosaminidases
  • Journal Article
  • Research Support, Non-U.S. Gov't


Dive into the research topics of 'Effective gene therapy in an authentic model of Tay-Sachs-related diseases'. Together they form a unique fingerprint.

Cite this