AAV-directed persistent expression of a gene encoding anti-nicotine antibody for smoking cessation

Martin J. Hicks, Jonathan B. Rosenberg, Bishnu P. De, Odelya E. Pagovich, Colin N. Young, Jian Ping Qiu, Stephen M. Kaminsky, Neil R. Hackett, Stefan Worgall, Kim D. Janda, Robin L. Davisson, Ronald G. Crystal

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Abstract

Current strategies to help tobacco smokers quit have limited success as a result of the addictive properties of the nicotine in cigarette smoke. We hypothesized that a single administration of an adeno-associated virus (AAV) gene transfer vector expressing high levels of an anti-nicotine antibody would persistently prevent nicotine from reaching its receptors in the brain. To test this hypothesis, we constructed an AAVrh.10 vector that expressed a full-length, high-affinity, anti-nicotine antibody derived from the Fab fragment of the anti-nicotine monoclonal antibody NIC9D9 (AAVantiNic). In mice treated with this vector, blood concentrations of the antinicotine antibody were dose-dependent, and the antibody showed high specificity and affinity for nicotine. The antibody shielded the brain from systemically administered nicotine, reducing brain nicotine concentrations to 15% of those in naïve mice. The amount of nicotine sequestered in the serum of vector-treated mice was more than seven times greater than that in untreated mice, with 83% of serum nicotine bound to immunoglobulin G. Treatment with the AAVantiNic vector blocked nicotine-mediated alterations in arterial blood pressure, heart rate, and locomotor activity. In summary, a single administration of a gene transfer vector expressing a high-affinity anti-nicotine monoclonal antibody elicited persistent (18 weeks), high titers of an anti-nicotine antibody that obviated the physiologic effects of nicotine. If this degree of efficacy translates to humans, AAVantiNic could be an effective preventative therapy for nicotine addiction.

Original languageEnglish
Article number140ra87
JournalScience Translational Medicine
Volume4
Issue number140
DOIs
Publication statusPublished - 27 Jun 2012

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Hicks, M. J., Rosenberg, J. B., De, B. P., Pagovich, O. E., Young, C. N., Qiu, J. P., Kaminsky, S. M., Hackett, N. R., Worgall, S., Janda, K. D., Davisson, R. L., & Crystal, R. G. (2012). AAV-directed persistent expression of a gene encoding anti-nicotine antibody for smoking cessation. Science Translational Medicine, 4(140), [140ra87]. https://doi.org/10.1126/scitranslmed.3003611