677. Gene Delivery of TNFR:Fc by Adeno-Associated Virus Vector Blocks Progression of Periodontitis

Although periodontitis is initiated by specific oral pathogens that colonize and invade the oral tissues, the host inflammatory response is a major factor in disease progression. Soluble protein delivery of antagonists to tumor necrosis factor alpha (TNF-receptor:Fc fusion protein) inhibit alveolar bone resorption. However, the clinical use of recombinant p75-TNFR:Fc fusion protein raises several concerns, such as reoccurrence of disease activity after cessation of therapy. Objectives: This pilot study used adeno-associated virus (AAV) as a mode to deliver the TNFR:Fc transgene to periodontal lesions in an experimental model of P. gingivalis LPS-mediated bone loss. Methods: Three groups of Sprague-Dawley rats received one of three treatments: LPS delivered to the maxillary interdental gingivae thrice weekly for 8 weeks; vehicle alone (PBS) or LPS plus the single local delivery of pseudotyped AAV[2/5]-TNFR:Fc vector [6 sites|[times]|15uL of 8|[times]|1011 DNase I-resistant particles (DRP)] at baseline. Microcomputed tomography (MicroCT), systemic blood levels of TNFR:Fc protein and cytokine profiles were performed at various timepoints ranging from baseline to 8 weeks following TNFR:Fc transgene delivery. Results: TNFR protein serum levels were low to undetectable in all groups over the entire observation period indicating that local vector delivery did not result in systemic distribution of the soluble TNFR:Fc protein. Real-time PCR showed higher expression of both TNFR1 and TNFR2 than controls (p<0.05) for AAV[2/5]-TNFR-treated animals. In addition, local delivery of AAV[2/5]-TNFR:Fc resulted in protection against LPS-mediated bone loss (mean linear bone loss: AAV-TNFR:Fc=0.68mm similar to PBS=0.71mm) while the LPS alone group demonstrated severe alveolar bone resorption 70-100% of root length (LPS=1.27mm; p<0.05). Conclusion: This proof-of-principle investigation suggests that local delivery of AAV[2/5]-TNFR:Fc vector can block alveolar bone loss for extended periods of time in the face of continual challenge of P. gingivalis LPS.