Intracerebroventricular delivery of glucocerebrosidase reduces substrates and increases lifespan in a mouse model of neuronopathic Gaucher disease

• Published in: Experimental neurology Vol. 225; no. 2; pp. 436 - 444
• Main Authors: Cabrera-Salazar, M.A., Bercury, S.D., Ziegler, R.J., Marshall, J., Hodges, B.L., Chuang, W.-L., Pacheco, J., Li, L., Cheng, S.H., Scheule, R.K.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01-10-2010; Elsevier
• Subjects: Animals; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Brain - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Gaucher Disease - enzymology; Gaucher Disease - genetics; Gaucher Disease - pathology; Genetic Vectors; Glucocerebrosidase; Glucosylceramidase - administration & dosage; Glucosylceramidase - genetics; Glucosylceramidase - metabolism; Glucosylceramide; Glucosylsphingosine; Immunohistochemistry; Injections, Intraventricular; Intracerebroventricular; Kaplan-Meier Estimate; Longevity - drug effects; Medical sciences; Mice; Neurology; Neuronopathic Gaucher disease; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Recombinant Proteins - administration & dosage; Recombinant Proteins - metabolism; Intracerebroventricular; Neuronopathic Gaucher disease; rhGC; IP; CNS; NGD; GluSph; GFAP; GluCer; Glucocerebrosidase; AAV; Glucosylceramide; ICV; WT; FJC; Glucosylsphingosine; Animal model; Nervous system diseases; Metabolic diseases; Lipids; Enzymopathy; Genetic disease; Cerebral disorder; Gaucher disease; Central nervous system disease; Lipoidosis
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2010.07.023

Gaucher disease is caused by a deficit in the enzyme glucocerebrosidase. As a consequence, degradation of the glycolipids glucosylceramide (GluCer) and glucosylsphingosine (GluSph) is impaired, and their subsequent buildup can lead to significant pathology and early death. Type 1 Gaucher patients can be treated successfully with intravenous replacement enzyme, but this enzyme does not reach the CNS and thus does not ameliorate the neurological involvement in types 2 and 3 Gaucher disease. As one potential approach to treating these latter patients, we have evaluated intracerebroventricular (ICV) administration of recombinant human glucocerebrosidase (rhGC) in a mouse model of neuronopathic Gaucher disease. ICV administration resulted in enzyme distribution throughout the brain and alleviated neuropathology in multiple brain regions of this mouse model. Treatment also resulted in dose-dependent decreases in GluCer and GluSph and significantly extended survival. To evaluate the potential of continuous enzyme delivery, a group of animals was treated ICV with an adeno-associated viral vector encoding hGC and resulted in a further extension of survival. These data suggest that ICV administration of rhGC may represent a potential therapeutic approach for type 2/3 Gaucher patients. Preclinical evaluation in larger animals will be needed to ascertain the translatability of this approach to the clinic.
►Intracerebroventricular delivered glucocerebrosidase distributes widely in the brain of a neonatal Gaucher model. ►Intracerebroventricular delivered glucocerebrosidase facilitates clearance of GluCer and GluSph. ►Glucocerebrosidase administration ameliorates CNS pathology. ►Dose-dependent substrate reduction correlates with increased lifespan.