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

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.

• 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)

Chemical References

• Antibodies, Neutralizing
• Antibodies, Viral
• Glycosaminoglycans
• enhanced green fluorescent protein
• Green Fluorescent Proteins
• N-Acetylgalactosamine-4-Sulfatase

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