Document Detail

Gene therapy for mucopolysaccharidosis type VI is effective in cats without pre-existing immunity to AAV8.
MedLine Citation:
PMID:  23194248     Owner:  NLM     Status:  MEDLINE    
Liver gene transfer with adeno-associated viral (AAV) 2/8 vectors is being considered for therapy of systemic diseases like mucopolysaccharidosis type VI (MPS VI), a lysosomal storage disease due to deficiency of arylsulfatase B (ARSB). We have previously reported that liver gene transfer with AAV2/8 results in sustained yet variable expression of ARSB. We hypothesized that the variability we observed could be due to pre-existing immunity to wild-type AAV8. To test this, we compared the levels of AAV2/8-mediated transduction in MPS VI cats with and without pre-existing immunity to AAV8. In addition, since levels of lysosomal enzymes as low as 5% of normal are expected to be therapeutic, we evaluated the impact of pre-existing immunity on MPS VI phenotypic rescue. AAV2/8 administration to MPS VI cats without pre-existing neutralizing antibodies to AAV8 resulted in consistent and dose-dependent expression of ARSB, urinary glycosaminoglycan (GAG) reduction, and femur length amelioration. Conversely, animals with pre-existing immunity to AAV8 showed low levels of ARSB expression and limited phenotypic improvement. Our data support the use of AAV2/8-mediated gene transfer for MPS VI and other systemic diseases, and highlight that pre-existing immunity to AAV8 should be considered in determining subject eligibility for therapy.
Rita Ferla; Thomas O'Malley; Roberto Calcedo; Patricia O'Donnell; Ping Wang; Gabriella Cotugno; Pamela Claudiani; James M Wilson; Mark Haskins; Alberto Auricchio
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-30
Journal Detail:
Title:  Human gene therapy     Volume:  24     ISSN:  1557-7422     ISO Abbreviation:  Hum. Gene Ther.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-20     Completed Date:  2013-09-10     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  9008950     Medline TA:  Hum Gene Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  163-9     Citation Subset:  IM    
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MeSH Terms
Antibodies, Neutralizing / immunology
Antibodies, Viral / immunology
Dependovirus / genetics,  immunology*
Dose-Response Relationship, Drug
Enzyme Activation
Femur / anatomy & histology
Gene Transfer Techniques
Genetic Therapy / methods*
Genetic Vectors / administration & dosage
Glycosaminoglycans / urine
Green Fluorescent Proteins / metabolism
Liver / enzymology
Mucopolysaccharidosis VI / immunology,  therapy*
N-Acetylgalactosamine-4-Sulfatase / blood,  genetics
Grant Support
DK25759/DK/NIDDK NIH HHS; P30-DK047757/DK/NIDDK NIH HHS; P40 OD010939/OD/NIH HHS; P40 RR002512/RR/NCRR NIH HHS; RR02512/RR/NCRR NIH HHS; TGM11MT6//Telethon
Reg. No./Substance:
0/Antibodies, Neutralizing; 0/Antibodies, Viral; 0/Glycosaminoglycans; 0/enhanced green fluorescent protein; 147336-22-9/Green Fluorescent Proteins; EC

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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