Periodontitis is one of the most common inflammatory diseases that afflict humans. The disease is the major cause of tooth loss in adults, affects >50% of the U.S. population, and is treated mainly by local debridement or surgery of the affected teeth. Although the disease is initiated by specific oral pathogens that colonize and invade the oral tissues, the host inflammatory response is a major factor in disease progression. Cytokines such as tumor necrosis factor-alpha (TNF) are found in high levels at periodontal lesions. Soluble protein delivery of antagonists to TNF (TNF receptor: Fc fusion protein) inhibits alveolar bone resorption. Nevertheless, the clinical use of recombinant p75 TNFR: Fc fusion protein raises several concerns, such as reoccurrence of disease activity after cessation of therapy (in the case of rheumatoid arthritis), injection site reactions, and the potential impairment of host immune function. We propose the use of adeno-associated virus (AAV) as an innovative approach to deliver TNFR: Fc to periodontal lesions. As a vector, AAV is a nonpathogenic human virus, and possesses the highly attractive feature of its minimal immunogenicity that allows for long-term transduction. AAV-TNFR: Fc generates the expression of the TNFR: Fc fusion protein, which functions as a TNF antagonist. This proof-of-principle study is designed to determine whether gene delivery of TNFR: Fc in an AAV vector can prevent periodontal disease progression in an experimental animal model of alveolar bone loss.
The Specific Aims of this study are to: 1) Determine serum levels and duration of TNFR: Fc protein expression following systemic (intramuscular) and local (interdental gingival tissue) administration of pseudotyped AAV-TNFR: Fc vectors to rats afflicted with LPS-induced periodontitis; and 2) Evaluate the effect of pseudotyped AAV-TNFR: Fc vectors on periodontal bone loss and expression of downstream proinflammatory cytokines in rats with LPS-induced periodontitis. These studies will determine the feasibility of this novel TNFR: Fc delivery strategy to modulate the host response for periodontal disease. The use of AAV-TNF: Fc has significant potential as a therapeutic regimen to treat aggressive periodontitis that is governed by an exuberant inflammatory response.
|Cirelli, J A; Park, C H; MacKool, K et al. (2009) AAV2/1-TNFR:Fc gene delivery prevents periodontal disease progression. Gene Ther 16:426-36|
|Havens, Aaron M; Chiu, Evonne; Taba, Mario et al. (2008) Stromal-derived factor-1alpha (CXCL12) levels increase in periodontal disease. J Periodontol 79:845-53|
|Park, Chan Ho; Abramson, Zachary R; Taba Jr, Mario et al. (2007) Three-dimensional micro-computed tomographic imaging of alveolar bone in experimental bone loss or repair. J Periodontol 78:273-81|
|Dunn, Matthew D; Park, Chan Ho; Kostenuik, Paul J et al. (2007) Local delivery of osteoprotegerin inhibits mechanically mediated bone modeling in orthodontic tooth movement. Bone 41:446-55|
|Kirkwood, Keith L; Cirelli, Joni A; Rogers, Jill E et al. (2007) Novel host response therapeutic approaches to treat periodontal diseases. Periodontol 2000 43:294-315|
|Rogers, Jill E; Li, Fei; Coatney, Derek D et al. (2007) Actinobacillus actinomycetemcomitans lipopolysaccharide-mediated experimental bone loss model for aggressive periodontitis. J Periodontol 78:550-8|
|Mao, J J; Giannobile, W V; Helms, J A et al. (2006) Craniofacial tissue engineering by stem cells. J Dent Res 85:966-79|
|Ramseier, Christoph A; Abramson, Zachary R; Jin, Qiming et al. (2006) Gene therapeutics for periodontal regenerative medicine. Dent Clin North Am 50:245-63, ix|