title: 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.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), 80131 Naples, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Ferla
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Malley
authors.forename: Roberto
authors.initials: R
authors.lastname: Calcedo
authors.forename: Patricia
authors.initials: P
authors.lastname: O'Donnell
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Gabriella
authors.initials: G
authors.lastname: Cotugno
authors.forename: Pamela
authors.initials: P
authors.lastname: Claudiani
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
authors.forename: Mark
authors.initials: M
authors.lastname: Haskins
authors.forename: Alberto
authors.initials: A
authors.lastname: Auricchio
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D002415:Cats; D000229:Dependovirus / Q000235:genetics / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005269:Femur / Q000033:anatomy & histology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006025:Glycosaminoglycans / Q000652:urine; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D009087:Mucopolysaccharidosis VI / Q000276:immunology / Q000628:therapy*; D020051:N-Acetylgalactosamine-4-Sulfatase / Q000097:blood / Q000235:genetics; D010641:Phenotype
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D006025:Glycosaminoglycans; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D020051:N-Acetylgalactosamine-4-Sulfatase