title: Hepatic gene transfer in neonatal mice by adeno-associated virus serotype 8 vector.
abstract: For genetic diseases that manifest at a young age with irreversible consequences, early treatment is critical and essential. Neonatal gene therapy has the advantages of achieving therapeutic effects before disease manifestation, a low vector requirement and high vector-to-cell ratio, and a relatively immature immune system. Therapeutic effects or long-term rescue of neonatal lethality have been demonstrated in several animal models. However, vigorous cell proliferation in the newborn stage is a significant challenge for nonintegrating vectors, such as adeno-associated viral (AAV) vector. Slightly delaying the injection age, and readministration at a later time, are two of the alternative strategies to solve this problem. In this study, we demonstrated robust and efficient hepatic gene transfer by self-complementary AAV8 vector in neonatal mice. However, transduction quickly decreased over a few weeks because of vector dilution caused by fast proliferation. Delaying the injection age improved sustained expression, although it also increased neutralizing antibody (NAb) responses to AAV capsid. This approach can be used to treat genetic diseases with slow progression. For genetic diseases with early onset and severe consequences, early treatment is essential. A second injection of vector of a different serotype at a later time may overcome preexisting NAb and achieve sustained therapeutic effects.
authors.affiliation: Gene Therapy Program, and Division of Transfusion Medicine, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.forename: Peter
authors.initials: P
authors.lastname: Bell
authors.forename: Deirdre
authors.initials: D
authors.lastname: McMenamin
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D002213:Capsid / Q000276:immunology; D000229:Dependovirus; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008099:Liver; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D014161:Transduction, Genetic
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D049452:Green Fluorescent Proteins
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