TNFR:Fc Gene Transfer for Treatment of Periodontitis

牙周炎是困扰人类的最常见的炎症性疾病之一。这种疾病是成人牙齿脱落的主要原因，影响着美国50%的人口，主要通过局部清创或手术治疗。虽然这种疾病是由定植和侵袭口腔组织的特定口腔病原体引起的，但宿主的炎症反应是疾病进展的主要因素。在牙周病变中发现高水平的细胞因子，如肿瘤坏死因子-α。可溶性肿瘤坏死因子拮抗剂(肿瘤坏死因子受体：Fc融合蛋白)可抑制牙槽骨吸收。然而，重组p75 TNFR：Fc融合蛋白的临床应用引起了几个问题，如停止治疗后疾病活动的复发(对于类风湿性关节炎)，注射部位反应，以及潜在的宿主免疫功能损害。我们建议使用腺相关病毒(AAV)作为一种创新的方法来将TNFR：Fc转移到牙周病变。作为一种载体，AAV是一种非致病性的人类病毒，具有免疫原性极低，允许长期转导的极具吸引力的特点。AAV-TNFR：Fc产生TNFR：Fc融合蛋白的表达，该融合蛋白具有肿瘤坏死因子拮抗剂的功能。这项原则验证研究旨在确定在牙槽骨丢失的实验动物模型中，将TNFR：Fc基因导入AAV载体是否可以防止牙周病的进展。本研究的具体目的是：1)检测脂多糖诱导的牙周炎大鼠全身(肌肉内)和局部(牙间牙龈组织)注射假AAV-TNFR：Fc载体后，血清中TNFR：Fc蛋白的表达水平和持续时间；2)评价假型AAV-TNFR：Fc载体对脂多糖诱导的牙周炎大鼠牙周骨丢失及下游促炎细胞因子表达的影响。这些研究将确定这种新的TNFR：FC递送策略调节宿主对牙周病反应的可行性。使用AAV-TNF：Fc作为一种治疗侵袭性牙周炎的治疗方案有很大的潜力，这种牙周炎是由旺盛的炎症反应控制的。

DESCRIPTION: 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.