AAVrh10 Gene Therapy Ameliorates Central and Peripheral Nervous System Disease in Canine Globoid Cell Leukodystrophy (Krabbe Disease)

Allison M. Bradbury, Mohammed A. Rafi, Jessica H. Bagel, Becky K. Brisson, Michael S. Marshall, Jill Pesayco Salvador, Xuntain Jiang, Gary P. Swain, Maria L. Prociuk, Patricia A. Odonnell, Caitlin Fitzgerald, Daniel S. Ory, Ernesto R. Bongarzone, G. Diane Shelton, David A. Wenger, Charles H. Vite

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39 Scopus citations


Globoid cell leukodystrophy (GLD), or Krabbe disease, is an inherited, neurologic disorder that results from deficiency of a lysosomal enzyme, galactosylceramidase. Most commonly, deficits of galactosylceramidase result in widespread central and peripheral nervous system demyelination and death in affected infants typically by 2 years of age. Hematopoietic stem-cell transplantation is the current standard of care in children diagnosed prior to symptom onset. However, disease correction is incomplete. Herein, the first adeno-associated virus (AAV) gene therapy experiments are presented in a naturally occurring canine model of GLD that closely recapitulates the clinical disease progression, neuropathological alterations, and biochemical abnormalities observed in human patients. Adapted from studies in twitcher mice, GLD dogs were treated by combination intravenous and intracerebroventricular injections of AAVrh10 to target both the peripheral and central nervous systems. Combination of intravenous and intracerebroventricular AAV gene therapy had a clear dose response and resulted in delayed onset of clinical signs, extended life-span, correction of biochemical defects, and attenuation of neuropathology. For the first time, therapeutic effect has been established in the canine model of GLD by targeting both peripheral and central nervous system impairments with potential clinical implications for GLD patients.

Original languageEnglish
Pages (from-to)785-801
Number of pages17
JournalHuman Gene Therapy
Issue number7
StatePublished - Jul 2018


  • AAV gene therapy
  • canine model
  • globoid cell leukodystrophy (Krabbe disease)
  • leukodystrophy
  • lysosomal storage disorder
  • neurodegenerative disease


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