Abstract |
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.
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Authors | Rita Ferla, Thomas O'Malley, Roberto Calcedo, Patricia O'Donnell, Ping Wang, Gabriella Cotugno, Pamela Claudiani, James M Wilson, Mark Haskins, Alberto Auricchio |
Journal | Human gene therapy
(Hum Gene Ther)
Vol. 24
Issue 2
Pg. 163-9
(Feb 2013)
ISSN: 1557-7422 [Electronic] United States |
PMID | 23194248
(Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibodies, Neutralizing
- Antibodies, Viral
- Glycosaminoglycans
- enhanced green fluorescent protein
- Green Fluorescent Proteins
- N-Acetylgalactosamine-4-Sulfatase
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Topics |
- Animals
- Antibodies, Neutralizing
(immunology)
- Antibodies, Viral
(immunology)
- Cats
- 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)
- Phenotype
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