Gene therapy for mucopolysaccharidosis type VI is effective in cats without pre-existing immunity to AAV8
| Autor: | Alberto Auricchio, Roberto Calcedo, Gabriella Cotugno, Rita Ferla, Mark E. Haskins, Patricia O'Donnell, Pamela Claudiani, Ping Wang, Thomas O'Malley, James M. Wilson |
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| Přispěvatelé: | Ferla, R, O'Malley, T, Calcedo, R, O'Donnell, P, Wang, P, Cotugno, G, Claudiani, P, Wilson, Jm, Haskins, M, Auricchio, Alberto |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Arylsulfatase B
N-Acetylgalactosamine-4-Sulfatase Genetic enhancement viruses Mucopolysaccharidosis type VI Genetic Vectors Green Fluorescent Proteins Biology Antibodies Viral Immunity Genetics Lysosomal storage disease medicine Animals Femur Molecular Biology Research Articles Glycosaminoglycans Mucopolysaccharidosis VI Dose-Response Relationship Drug Gene Transfer Techniques Genetic Therapy Dependovirus medicine.disease Antibodies Neutralizing Enzyme Activation Phenotype Liver Immunology biology.protein Cats Molecular Medicine Antibody |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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