Gene therapy for mucopolysaccharidosis type VI is effective in cats without pre-existing immunity to AAV8

• Published in: Human gene therapy Vol. 24; no. 2; p. 163
• Main Authors: Ferla, Rita, O'Malley, Thomas, Calcedo, Roberto, O'Donnell, Patricia, Wang, Ping, Cotugno, Gabriella, Claudiani, Pamela, Wilson, James M, Haskins, Mark, Auricchio, Alberto
• Format: Journal Article
• Language: English
• Published: United States 01.02.2013
• Subjects: Animals; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Cats; Dependovirus - genetics; Dependovirus - 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; Mucopolysaccharidosis VI - therapy; N-Acetylgalactosamine-4-Sulfatase - blood; N-Acetylgalactosamine-4-Sulfatase - genetics; Phenotype
• ISSN: 1557-7422
• DOI: 10.1089/hum.2012.179

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.