title: Prevalence of AAV1 neutralizing antibodies and consequences for a clinical trial of gene transfer for advanced heart failure.
abstract: Adeno-associated virus serotype 1 (AAV1) has many advantages as a gene therapy vector, but the presence of pre-existing neutralizing antibodies (NAbs) is an important limitation. This study was designed to determine: (1) characteristics of AAV NAbs in human subjects, (2) prevalence of AAV1 NAbs in heart failure patients and (3) utility of aggressive immunosuppressive therapy in reducing NAb seroconversion in an animal model. NAb titers were assessed in a cohort of heart failure patients and in patients screened for a clinical trial of gene therapy with AAV1 carrying the sarcoplasmic reticulum calcium ATPase gene (AAV1/SERCA2a). AAV1 NAbs were found in 59.5% of 1552 heart failure patients. NAb prevalence increased with age (P=0.001) and varied geographically. The pattern of NAb titers suggested that exposure is against AAV2, with AAV1 NAb seropositivity due to crossreactivity. The effects of immunosuppression on NAb formation were tested in mini-pigs treated with immunosuppressant therapy before, during and after a single AAV1/SERCA2a infusion. Aggressive immunosuppression did not prevent formation of AAV1 NAbs. We conclude that immunosuppression is unlikely to be a viable solution for repeat AAV1 dosing. Strategies to reduce NAbs in heart failure patients are needed to increase eligibility for gene transfer using AAV vectors.
authors.affiliation: Sulpizio Cardiovascular Center, University of California, San Diego, La Jolla, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Greenberg
authors.affiliation: Stony Brook University, Stony Brook, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Butler
authors.affiliation: Duke University School of Medicine, Durham, NC, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Felker
authors.affiliation: Wroclaw Medical University and Military Hospital, Wroclaw, Poland.
authors.forename: P
authors.initials: P
authors.lastname: Ponikowski
authors.affiliation: University of Groningen, Groningen, The Netherlands.
authors.forename: A A
authors.initials: AA
authors.lastname: Voors
authors.affiliation: Celladon Corporation, San Diego, CA, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Pogoda
authors.affiliation: Celladon Corporation, San Diego, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Provost
authors.affiliation: Celladon Corporation, San Diego, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Guerrero
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Hajjar
authors.affiliation: Biovest Consulting, LLC, Santa Barbara, CA, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Zsebo
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology*; D000229:Dependovirus / Q000235:genetics* / Q000276:immunology*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000276:immunology*; D006333:Heart Failure / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D023421:Models, Animal; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013552:Swine; D013556:Swine, Miniature
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases