TNFR:Fc Gene Transfer for Treatment of Periodontitis

描述：牙周炎是一种最常见的炎症性疾病，折磨人类。该疾病是成年人牙齿脱落的主要原因，影响>50%的美国人口，并且主要通过受影响牙齿的局部清创或手术来治疗。虽然疾病是由特定的口腔病原体引起的，这些病原体定殖并侵入口腔组织，但宿主的炎症反应是疾病进展的主要因素。细胞因子如肿瘤坏死因子-α（TNF）在牙周病变中的水平很高。TNF拮抗剂（TNF受体：Fc融合蛋白）的可溶性蛋白递送抑制牙槽骨吸收。然而，重组p75 TNFR：Fc融合蛋白的临床应用引起了一些担忧，例如停止治疗后疾病活动的复发（在类风湿性关节炎的情况下）、注射部位反应和宿主免疫功能的潜在损害。我们建议使用腺相关病毒（AAV）作为一种创新的方法，提供TNFR：Fc牙周病变。作为一种载体，AAV是一种非致病性的人类病毒，并且具有高度吸引人的特征，即其最小的免疫原性，允许长期转导。AAV-TNFR：Fc产生TNFR：Fc融合蛋白的表达，其充当TNF拮抗剂。这项原理验证研究旨在确定在腺相关病毒载体中TNFR：Fc的基因递送是否可以在牙槽骨丢失的实验动物模型中预防牙周病进展。本研究的具体目的是：1）确定全身性给药后TNFR：Fc蛋白表达的血清水平和持续时间。（肌内）和局部（齿间牙龈组织）向患有LPS诱导的牙周炎的大鼠施用假型AAV-TNFR：Fc载体;和2）评估假型AAV-TNFR：Fc载体的作用：Fc载体对脂多糖诱导的牙周炎大鼠牙周骨丢失和下游促炎细胞因子表达的影响这些研究将确定这种新型TNFR：Fc递送策略调节牙周病宿主反应的可行性。AAV-TNF的使用：Fc作为一种治疗方案具有显著的潜力来治疗由旺盛的炎症反应控制的侵袭性牙周炎。

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.