Successful Expression of Human Factor IX Following Repeat Administration of an Adenoviral Vector in Mice

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 93; no. 7; pp. 3056 - 3061
• Main Authors: Walter, Johannes, You, Qimin, Hagstrom, J. Nathan, Sands, Mark, High, Katherine A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 02.04.1996; National Acad Sciences; National Academy of Sciences
• Subjects: Adenoviridae - genetics; Adenoviridae - immunology; adenovirus; Adenoviruses; Adults; Animals; Animals, Newborn; Antibodies; Antibodies, Viral - biosynthesis; Antibodies, Viral - blood; beta-Galactosidase - analysis; beta-Galactosidase - biosynthesis; Blood plasma; Factor IX - analysis; Factor IX - biosynthesis; Factor IX - genetics; Female; Gene Expression; Genetic Vectors; Humans; Immunity (Disease); Intravenous injections; Kinetics; Lac Operon; Liver; Male; Mice; Mice, Inbred Strains; Neutralizing antibodies; Recombinant Proteins - biosynthesis; Recombinant Proteins - blood; Rodents; Time Factors; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.93.7.3056

Adenoviral vectors can direct high-level expression of a transgene, but, due to a host immune response to adenoviral antigens, expression is of limited duration, and repetitive administration has generally been unsuccessful. Exposure to foreign proteins beginning in the neonatal period may alter or ablate the immune response. We injected adult and neonatal (immunocompetent) CD-1 mice intravenously with an adenoviral vector expressing human blood coagulation factor IX. In both groups of mice, expression of human factor IX persisted for 12-16 weeks. However, in mice initially injected as adults, repeat administration of the vector resulted in no detectable expression of the transgene, whereas in mice initially injected in the neonatal period, repeat administration resulted in high-level expression of human factor IX. We show that animals that fail to express the transgene on repeat administration have developed high-titer neutralizing antibodies to adenovirus, whereas those that do express factor IX have not. This experimental model suggests that newborn mice can be tolerized to adenoviral vectors and demonstrates that at least one repeat injection of the adenoviral vector is possible; the model will be useful in elucidating the immunologic mechanisms underlying successful repeat administration of adenoviral vectors.