HOPE FOR TREATING KRABBE DISEASE

摘要

Globoid cell leukodystrophy (GLD), or Krabbe disease, results from a deficiency in the hydrolytic enzyme galactosylceramidase (GALC), which is responsible for degrading the central and peripheral nervous system myelin lipids galactosylceramide and galactosylsphingosine (psychosine).Combination gene therapy has been evaluated in GLD affected dogs using AAVrhlO encoding canine GALC (AAVrh10-cGALC). Two GLD dogs received a low dose of AAVrh10-cGALC, 1.2E12, by combination intravenous (IV) and intracerebroventricular (ICV) injection routes and displayed a modest increase in survival to 17.9 and 22.1 weeks of age. Two additional GLD dogs were treated with an increased dose of AAVrhl 0-cGALC, 1.9E13, and survival was further increased to 30.3 and 43.1 weeks of age. Both low and high dose combination IV and ICV therapy delayed the onset of neurological signs and prevented the onset of tremors. High dose AAVrhl 0-cGALC, but not low dose, resulted in normalization of pelvic and thoracic limb nerve conduction velocity and near normal sensory nerve conduction velocity. Combination therapy of either dose had negligible effect on the auditory system. After high dose treatment with AAVrhl 0-cGALC, GALC activity reached near normal levels in the cerebellum and sciatic nerve. GLD dogs treated with high dose AAV had CSF psychosine concentrations lower than untreated and low dose AAV-treated GLD dogs, despite being substantially older.