title: Effect of viral dose on neutralizing antibody response and transgene expression after AAV1 vector re-administration in mice.
abstract: Neutralizing antibodies (nAB) at the time of administration hamper the effectiveness of adeno-associated virus (AAV) as a clinical DNA delivery system. The present study was designed to investigate if AAV re-administration in muscle tissue is dependent on the nAB titer. Recombinant (r)AAV serotype 1, as a promising candidate for targeting skeletal muscle, was used for gene delivery. C57Bl/6 mice were infected intramuscularly with doses between 1 x 10(9) and 5 x 10(10) virus particles (vp) of AAV1-expressing luciferase (AAV1-luc) or human interferon-beta (AAV1-hIFNbeta). Increasing transgene expression was observed over the first 2 months and anti-AAV1 nAB titers peaked between weeks 4 and 8. Six months after the first administration, 5 x 10(10) vp of AAV1-IFNbeta were re-administered. Following re-administration, nAB titers increased but did not significantly affect transgene expression from the AAV vector that had been administered first. In contrast, hIFNbeta expression originating from the second vector administration was significantly diminished and reflected the nAB titer present at the day of re-administration. The present study extends earlier observations that preexisting nAB affects AAV1 re-administration. The level of nAB is proportional to the virus dose used for the first injection and transgene expression following re-administration is dependent on preexisting nAB titer.
authors.affiliation: Department of Gene Technologies, Berlex Biosciences, Richmond, CA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Petry
authors.forename: A
authors.initials: A
authors.lastname: Brooks
authors.forename: A
authors.initials: A
authors.lastname: Orme
authors.forename: P
authors.initials: P
authors.lastname: Wang
authors.forename: P
authors.initials: P
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Xie
authors.forename: P
authors.initials: P
authors.lastname: Kretschmer
authors.forename: H S
authors.initials: HS
authors.lastname: Qian
authors.forename: T W
authors.initials: TW
authors.lastname: Hermiston
authors.forename: R N
authors.initials: RN
authors.lastname: Harkins
mesh_terms: D000818:Animals; D000906:Antibodies / Q000032:analysis; D000917:Antibody Formation; D000229:Dependovirus / Q000235:genetics* / Q000276:immunology; D015870:Gene Expression; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000276:immunology; D006801:Humans; D007273:Injections, Intramuscular; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology; D008156:Luciferases / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods*; D019076:Transgenes; D019562:Viral Load
chemical_list: D000906:Antibodies; D016899:Interferon-beta; D008156:Luciferases