AAVrh10 gene therapy ameliorates central and peripheral nervous system disease in canine globoid cell leukodystrophy (Krabbe disease).

AAVrh10 gene therapy ameliorates central and peripheral nervous system disease in canine globoid cell leukodystrophy (Krabbe disease).

Hum Gene Ther. 2018 Jan 09;:

Authors: Bradbury AM, Rafi MA, Bagel J, Brisson BK, Marshall MS, Pesayco Salvador J, Jiang X, Swain GP, Prociuk ML, O'Donnell P, Fitzgerald C, Ory DS, Bongarzone ER, Shelton GD, Wenger DA, Vite C

Abstract
Globoid cell leukodystrophy (GLD), or Krabbe disease, is an inherited, neurologic disorder that results from deficiency of a lysosomal enzyme, galactosylceramidase (GALC). Most commonly, deficits of GALC result in widespread central and peripheral nervous system (CNS, PNS) 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 we present the first adeno-associated virus (AAV) gene therapy experiments 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 the twitcher mice, GLD dogs were treated by combination intravenous (IV) and intracerebroventricular (ICV) injections of AAVrh10 to target both PNS and CNS. Combination of IV and ICV AAV gene therapy had a clear dose response and resulted in delayed onset of clinical signs, extended lifespan, correction of biochemical defects, and attenuation of neuropathology. For the first time we have established therapeutic effect in the canine model of GLD by targeting both peripheral and central nervous system impairments with potential clinical implications for GLD patients.

PMID: 29316812 [PubMed - as supplied by publisher]

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