AAV-Directed Persistent Expression of a Gene Encoding Anti-Nicotine Antibody for Smoking Cessation

Sci Transl Med 27 June 2012:
Vol. 4, Issue 140, p. 140ra87
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3003611

• Research Article

Addiction

AAV-Directed Persistent Expression of a Gene Encoding Anti-Nicotine Antibody for Smoking Cessation

1. Martin J. Hicks¹,*,^†,
2. Jonathan B. Rosenberg¹,*,
3. Bishnu P. De¹,*,
4. Odelya E. Pagovich¹,
5. Colin N. Young²,
6. Jian-ping Qiu¹,
7. Stephen M. Kaminsky¹,
8. Neil R. Hackett¹,
9. Stefan Worgall¹,³,
10. Kim D. Janda⁴,
11. Robin L. Davisson²,⁵ and
12. Ronald G. Crystal¹

+ Author Affiliations

1. ¹Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
2. ²Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14850, USA.
3. ³Department of Pediatrics, Weill Cornell Medical College, New York, NY 10065, USA.
4. ⁴Departments of Chemistry and Immunology and Microbial Science, Scripps Research Institute, La Jolla, CA 92037, USA.
5. ⁵Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA.

+ Author Notes

• ↵* These authors contributed equally to this work.

1. ↵†To whom correspondence should be addressed. E-mail: geneticmedicine@med.cornell.edu

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 anti-nicotine 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.

• Copyright © 2012, American Association for the Advancement of Science

Citation: M. J. Hicks, J. B. Rosenberg, B. P. De, O. E. Pagovich, C. N. Young, J.-p. Qiu, S. M. Kaminsky, N. R. Hackett, S. Worgall, K. D. Janda, R. L. Davisson, R. G. Crystal, AAV-Directed Persistent Expression of a Gene Encoding Anti-Nicotine Antibody for Smoking Cessation. Sci. Transl. Med. 4, 140ra87 (2012).

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