title: Human immunoglobulin inhibits liver transduction by AAV vectors at low AAV2 neutralizing titers in SCID mice.
abstract: Long-term cures of hemophilia B have been achieved using AAV2 delivering the factor IX gene to the liver of adeno-associated virus (AAV)-naive hemophilic animals. However, the clinical success of this approach requires overcoming pre-existing AAV neutralizing antibodies prevalent in humans. To better define the inhibition of neutralizing antibodies on AAV2-mediated liver transduction, we developed an in vivo passive immunity model. SCID mice were first reconstituted to a defined neutralizing titer with pooled plasma-derived human immunoglobulin. AAV2-FIX vectors then were administered to the liver, and the transduction efficiency was measured by plasma FIX levels. Unexpectedly, AAV2 neutralizing titers lower than 1:10 were sufficient to neutralize 4 to 20 x 10(12) vg/kg of AAV2 vectors in vivo, a capacity that was underestimated by in vitro neutralizing assays. We also evaluated strategies to evade neutralization, including the use of alternative delivery routes, infusion parameters, empty capsids, and alternative AAV serotypes 6 and 8. The results indicate that low AAV2 neutralizing titers can be inhibitory to the tested human and primate AAV vectors delivered into the circulatory system. Therefore, novel nonprimate AAV vectors or compartmentalized delivery may offer more consistent therapeutic effects in the presence of pre-existing AAV neutralizing antibodies.
authors.affiliation: Avgen, Alameda, CA, USA. ciaran_scallan@yahoo.com
authors.forename: Ciaran D
authors.initials: CD
authors.lastname: Scallan
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiang
authors.forename: Tongyao
authors.initials: T
authors.lastname: Liu
authors.forename: Susannah
authors.initials: S
authors.lastname: Patarroyo-White
authors.forename: Jurg M
authors.initials: JM
authors.lastname: Sommer
authors.forename: Shangzhen
authors.initials: S
authors.lastname: Zhou
authors.forename: Linda B
authors.initials: LB
authors.lastname: Couto
authors.forename: Glenn F
authors.initials: GF
authors.lastname: Pierce
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D002213:Capsid / Q000276:immunology*; D000229:Dependovirus / Q000235:genetics / Q000276:immunology*; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D002836:Hemophilia B / Q000276:immunology / Q000628:therapy; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID
chemical_list: D000914:Antibodies, Viral; D016756:Immunoglobulins, Intravenous