TNFR:Fc Gene Transfer for Treatment of Periodontitis

TNFR：Fc 基因转移治疗牙周炎

• 批准号: 7045962
• 负责人: WILLIAM V GIANNOBILE
• 金额: $ 16.55万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7045962
• 关键词: adeno associated virus group; chimeric proteins; cytokine receptors; gene delivery system; inflammation; laboratory rat; periodontitis; transfection /expression vector; tumor necrosis factor alpha

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.

描述：牙周炎是困扰人类的最常见的炎症性疾病之一。该疾病是成人牙齿脱落的主要原因，影响超过 50% 的美国人口，主要通过受影响牙齿的局部清创或手术来治疗。尽管该疾病是由定殖并侵入口腔组织的特定口腔病原体引发的，但宿主炎症反应是疾病进展的主要因素。牙周病变处发现高水平的细胞因子，例如肿瘤坏死因子-α (TNF)。 TNF 拮抗剂（TNF 受体：Fc 融合蛋白）的可溶性蛋白递送可抑制牙槽骨吸收。然而，重组p75 TNFR:Fc融合蛋白的临床使用引起了一些担忧，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）、注射部位反应以及宿主免疫功能的潜在损害。我们建议使用腺相关病毒 (AAV) 作为一种创新方法，将 TNFR: Fc 递送至牙周病变。作为载体，AAV 是一种非致病性人类病毒，具有极低的免疫原性、可进行长期转导等极具吸引力的特征。 AAV-TNFR:Fc 产生 TNFR:Fc 融合蛋白的表达，其起到 TNF 拮抗剂的作用。这项原理验证研究旨在确定 AAV 载体中的 TNFR:Fc 基因传递是否可以预防牙槽骨丢失实验动物模型中的牙周病进展。本研究的具体目的是： 1) 确定对患有 LPS 诱导的大鼠进行全身（肌内）和局部（齿间牙龈组织）假型 AAV-TNFR：Fc 载体给药后 TNFR：Fc 蛋白表达的血清水平和持续时间牙周炎; 2) 评估假型 AAV-TNFR:Fc 载体对 LPS 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 递送策略调节宿主对牙周病反应的可行性。 AAV-TNF:Fc 作为一种治疗方案具有巨大的潜力，可以治疗由旺盛炎症反应控制的侵袭性牙周炎。