title: Immunological ignorance allows long-term gene expression after perinatal recombinant adeno-associated virus-mediated gene transfer to murine airways.
abstract: Gene therapy of the lung has the potential to treat life-threatening diseases such as cystic fibrosis and α(1)-antitrypsin or surfactant deficiencies. A major hurdle for successful gene therapy is the development of an immune response against the transgene and/or viral vector. We hypothesized that by targeting the airways in the perinatal period, induction of an immune response against the vector particle could be prevented because of immaturity of the immune system, in turn allowing repeated gene transfer later in adult life to ensure long-term gene expression. Therefore, we readministered recombinant adeno-associated viral vector serotype 5 (rAAV2/5) to mouse airways 3 and 6 months after initial perinatal gene transfer. Our findings demonstrate that perinatal rAAV2/5-mediated gene transfer to the airways avoids a strong immune response. This immunological ignorance allows the readministration of an autologous vector later in adult life, resulting in efficient and stable gene transfer up to 7 months, without evidence of a decrease in transgene expression. Together, these data provide a basis to further explore perinatal gene therapy for pulmonary conditions with adequate gene expression up to 7 months.
authors.affiliation: 1 Laboratory of Molecular Virology and Gene Therapy, Katholieke Universiteit (KU) Leuven , Leuven, Belgium .
authors.forename: Marianne S
authors.initials: MS
authors.lastname: Carlon
authors.forename: Dragana
authors.initials: D
authors.lastname: Vidović
authors.forename: James
authors.initials: J
authors.lastname: Dooley
authors.forename: Marina Mori
authors.initials: MM
authors.lastname: da Cunha
authors.forename: Michael
authors.initials: M
authors.lastname: Maris
authors.forename: Youlia
authors.initials: Y
authors.lastname: Lampi
authors.forename: Jaan
authors.initials: J
authors.lastname: Toelen
authors.forename: Chris
authors.initials: C
authors.lastname: Van den Haute
authors.forename: Veerle
authors.initials: V
authors.lastname: Baekelandt
authors.forename: Jan
authors.initials: J
authors.lastname: Deprest
authors.forename: Erik
authors.initials: E
authors.lastname: Verbeken
authors.forename: Adrian
authors.initials: A
authors.lastname: Liston
authors.forename: Rik
authors.initials: R
authors.lastname: Gijsbers
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D057134:Antibodies, Neutralizing / Q000502:physiology; D000914:Antibodies, Viral / Q000502:physiology; D002213:Capsid / Q000276:immunology; D000229:Dependovirus / Q000235:genetics / Q000276:immunology*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D012137:Respiratory System / Q000276:immunology* / Q000821:virology; D014161:Transduction, Genetic; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D001616:beta-Galactosidase