Document Detail

Safe, efficient, and reproducible gene therapy of the brain in the dog models of Sanfilippo and Hurler syndromes.
MedLine Citation:
PMID:  21139569     Owner:  NLM     Status:  MEDLINE    
Recent trials in patients with neurodegenerative diseases documented the safety of gene therapy based on adeno-associated virus (AAV) vectors deposited into the brain. Inborn errors of the metabolism are the most frequent causes of neurodegeneration in pre-adulthood. In Sanfilippo syndrome, a lysosomal storage disease in which heparan sulfate oligosaccharides accumulate, the onset of clinical manifestation is before 5 years. Studies in the mouse model showed that gene therapy providing the missing enzyme α-N-acetyl-glucosaminidase to brain cells prevents neurodegeneration and improves behavior. We now document safety and efficacy in affected dogs. Animals received eight deposits of a serotype 5 AAV vector, including vector prepared in insect Sf9 cells. As shown previously in dogs with the closely related Hurler syndrome, immunosuppression was necessary to prevent neuroinflammation and elimination of transduced cells. In immunosuppressed dogs, vector was efficiently delivered throughout the brain, induced α-N-acetyl-glucosaminidase production, cleared stored compounds and storage lesions. The suitability of the procedure for clinical application was further assessed in Hurler dogs, providing information on reproducibility, tolerance, appropriate vector type and dosage, and optimal age for treatment in a total number of 25 treated dogs. Results strongly support projects of human trials aimed at assessing this treatment in Sanfilippo syndrome.
N Matthew Ellinwood; Jérôme Ausseil; Nathalie Desmaris; Stéphanie Bigou; Song Liu; Jackie K Jens; Elizabeth M Snella; Eman E A Mohammed; Christopher B Thomson; Sylvie Raoul; Béatrice Joussemet; Françoise Roux; Yan Chérel; Yaouen Lajat; Monique Piraud; Rachid Benchaouir; Stephan Hermening; Harald Petry; Roseline Froissart; Marc Tardieu; Carine Ciron; Philippe Moullier; Jennifer Parkes; Karen L Kline; Irène Maire; Marie-Thérèse Vanier; Jean-Michel Heard; Marie-Anne Colle
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-12-07
Journal Detail:
Title:  Molecular therapy : the journal of the American Society of Gene Therapy     Volume:  19     ISSN:  1525-0024     ISO Abbreviation:  Mol. Ther.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-02-03     Completed Date:  2011-05-11     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  100890581     Medline TA:  Mol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  251-9     Citation Subset:  IM    
Department of Animal Science, Iowa State University, Ames, IA, USA.
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MeSH Terms
Acetylglucosaminidase / genetics
Brain / metabolism*,  pathology
Dependovirus / genetics
Disease Models, Animal
Genetic Therapy / adverse effects,  methods*
Genetic Vectors / genetics
Mucopolysaccharidosis I / therapy*
Mucopolysaccharidosis III / therapy*
Polymerase Chain Reaction
Reg. No./Substance:

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