Evaluation of AAV-mediated gene therapy for central nervous system disease in Canine Mucopolysaccharidosis VII

Brittney L. Gurda, Adrien De Guilhem De Lataillade, Peter Bell, Yanqing Zhu, Hongwei Yu, Ping Wang, Jessica Bagel, Charles H. Vite, Tracey Sikora, Christian Hinderer, Roberto Calcedo, Alexander D. Yox, Richard A. Steet, Therese Ruane, Patricia O'Donnell, Guangping Gao, James M. Wilson, Margret Casal, Katherine P. Ponder, Mark E. Haskins

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease arising from mutations in β-d-glucuronidase (GUSB), which results in glycosaminoglycan (GAG) accumulation and a variety of clinical manifestations including neurological disease. Herein, MPS VII dogs were injected intravenously (i.v.) and/or intrathecally (i.t.) via the cisterna magna with AAV9 or AAVrh10 vectors carrying the canine GUSB cDNA. Although i.v. injection alone at 3 days of age resulted in normal cerebrospinal fluid (CSF) GUSB activity, brain tissue homogenates had only ∼1 to 6% normal GUSB activity and continued to have elevated GAG storage. In contrast, i.t. injection at 3 weeks of age resulted in CSF GUSB activity 44-fold normal while brain tissue homogenates had >100% normal GUSB activity and reduced GAGs compared with untreated dogs. Markers for secondary storage and inflammation were eliminated in i.t.-treated dogs and reduced in i.v.-treated dogs compared with untreated dogs. Given that i.t.-treated dogs expressed higher levels of GUSB in the CNS tissues compared to those treated i.v., we conclude that i.t. injection of AAV9 or AAVrh10 vectors is more effective than i.v. injection alone in the large animal model of MPS VII.

Original languageEnglish
Pages (from-to)206-216
Number of pages11
JournalMolecular Therapy
Volume24
Issue number2
DOIs
StatePublished - Feb 1 2016

Fingerprint

Dive into the research topics of 'Evaluation of AAV-mediated gene therapy for central nervous system disease in Canine Mucopolysaccharidosis VII'. Together they form a unique fingerprint.

Cite this