title: AAV-directed persistent expression of a gene encoding anti-nicotine antibody for smoking cessation.
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.
authors: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA. geneticmedicine@med.cornell
authors: Martin J
authors: MJ
authors: Hicks
authors: Jonathan B
authors: JB
authors: Rosenberg
authors: Bishnu P
authors: BP
authors: De
authors: Odelya E
authors: OE
authors: Pagovich
authors: Colin N
authors: CN
authors: Young
authors: Jian-ping
authors: JP
authors: Qiu
authors: Stephen M
authors: SM
authors: Kaminsky
authors: Neil R
authors: NR
authors: Hackett
authors: Stefan
authors: S
authors: Worgall
authors: Kim D
authors: KD
authors: Janda
authors: Robin L
authors: RL
authors: Davisson
authors: Ronald G
authors: RG
authors: Crystal
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use*; D000229:Dependovirus / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009538:Nicotine / Q000276:immunology*; D016540:Smoking Cessation / Q000379:methods*
chemical_list: D000911:Antibodies, Monoclonal; D009538:Nicotine