Localized Delivery of a Novel Therapeutic Agent for Periodontal Disease

牙周病新型治疗剂的局部递送

• 批准号: 7219741
• 负责人: Diane Ellis-Edwards
• 金额: $ 15万
• 依托单位: ECI BIOTECH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7219741
• 关键词: Adult; Affect; American; Animal Model; Anti-Inflammatory Agents; Antibiotics; Bacteria; Bacterial Infections; Biochemistry; Biocompatible; Cell Death; Cell Survival; Cells; Chronic; Class; Clinical; Complex; Condition; Control Groups; Coronary heart disease; Coupled; Dental Calculus; Diagnostic; Disease; Disease Management; Dose; Drug Formulations; Endopeptidases; Enzymes; Epithelial Cells; Feasibility Studies; Fibroblasts; Gingiva; Gingival Pocket; Goals; Healed; Heating; Human; Hyaluronan; Immune response; In Vitro; Infection; Inflammatory; Inflammatory Response; Localized; Low Birth Weight Infant; Lung diseases; Matrix Metalloproteinases; Mediating; Metalloproteases; Methods; Microbe; Microbial Biofilms; Microspheres; Modeling; Mus; Oral; Other Therapy; Pain; Peptide Hydrolases; Peptides; Periodontal Diseases; Periodontitis; Phase; Phase I Clinical Trials; Physiological; Polystyrenes; Porphyromonas gingivalis; Premature Birth; Protease Inhibitor; Proteins; Rattus; Risk; Site; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Statistically Significant; Symptoms; System; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Tooth Loss; Tooth structure; Toxin; Treponema denticola; Virulence; antimicrobial drug; bone; bone loss; cell injury; corneal epithelium; diabetic; dosage; glycemic control; healing; in vivo; inhibitor/antagonist; kidney epithelial cell; microbial; microbial host; novel; novel therapeutics; oral pathogen; pathogen; prevent; protector protein; tissue culture

DESCRIPTION (provided by applicant): Human periodontal disease is a chronic condition that results from bacterial infection of the gingival and the associated inflammatory response. Recent studies estimate that between 35 to 45% of adults in the US have chronic periodontitis, with up to 90% having some form of periodontal disease. In addition to pain, discomfort, and tooth and oral bone damage, periodontal disease has been associated with an increased risk of systemic complications such as coronary heart disease. The primary etiologic agent of periodontitis, Poryphyromonas gingivalis, is closely associated with the onset of periodontal disease. This bacterium, along with the other major cohabitants of the "red complex" (Treponema denticola and Tannerella forsythensis), is sequestered as a biofilm in plaque or tartar during infection. Delivering therapeutic doses of antibiotics or anti-inflammatory agents over a sustained period of time is difficult and there are major clinical problems in management of this disease. Destruction of the gingival tissue in periodontitis is mediated in part by host- and microbe-derived protein- degrading enzymes called proteases. The long-term goal of this proposal is to develop a therapeutic agent that gives sustained delivery of a cell protective compound to the gingival pocket. This compound is a novel inhibitor of microbial and inflammatory proteases from a class of "Protector Peptides" characterized by ECI. When applied to gingival tissue, possibly in combination with an antimicrobial, this agent will protect tissue from further enzymatic damage, reduce the bacterial load, and aid in the resumption of healing. ECI has previously demonstrated that this compound, called heat gamma (HG), is an effective inhibitor of proteases produced by P. gingivalis and host matrix metalloproteases in vitro. HG also protected epithelial cells from bacteria-induced cell damage in a tissue culture model of infection. In this Phase I proposal, the activity of HG delivered on microbeads will be examined in feasibility studies for the final treatment formulation in Phase II. This formulation will consist of HG peptide incorporated into biodegradable hyaluronan microbeads that will be injected into the gingival pocket to provide sustained HG delivery. The Phase I objectives are to show that HG attached to microbeads can inhibit bacterial proteases from the three red complex pathogens in vitro and to examine their effect on a P. gingivalis biofilm (Aim 1). The next objective is to demonstrate the ability of HG microbeads to prevent cell death of gingival fibroblasts after P. gingivalis infection (Aim 2). Lastly, a mouse chamber model will be used to assess the ability of HG delivered on beads to reduce P. gingivalis virulence, viability, and the host inflammatory response in vivo (Aim 3).

描述（由申请人提供）：人类牙周疾病是一种慢性疾病，它是由牙龈细菌感染和相关炎症反应引起的。最近的研究估计，美国有35％至45％的成年人患有慢性牙周炎，高达90％的牙周疾病。除了疼痛，不适，牙齿和口腔骨骼损害外，牙周疾病还与诸如冠心病等全身并发症的风险增加有关。牙周炎的主要病因学药物，猪笼草牙龈毒性，与牙周疾病的发作密切相关。这种细菌以及“红色复合物”的其他主要同居者（treponema denticola和tannerella forsythensis）在感染过程中被隔离为斑块或塔塔尔中的生物膜。在持续的时间内输送治疗剂量的抗生素或抗炎药是很困难的，并且在这种疾病的管理中存在主要的临床问题。 牙周炎中牙龈组织的破坏部分是由称为蛋白酶的宿主和微生物衍生的蛋白质降解酶介导的。该提案的长期目标是开发一种治疗剂，该治疗剂可持续将细胞保护化合物递送到牙龈袋中。该化合物是来自ECI特征的一类“保护肽”的微生物和炎性蛋白酶的新型抑制剂。当应用于牙龈组织（可能与抗菌剂结合使用）时，该药物将保护组织免受进一步的酶促损伤，减少细菌载荷并有助于恢复愈合。 ECI先前已经证明，这种称为热伽马（HG）的化合物是在体外由牙龈疟原虫和宿主基质金属蛋白酶产生的蛋白酶的有效抑制剂。 HG还保护上皮细胞免受细菌诱导的感染模型中的细胞损伤。在这一阶段的建议中，将在II期最终治疗公式的可行性研究中检查对微头的HG活性。该配方将由掺入可生物降解的透明质酸微粒中的HG肽组成，这些肽将被注入牙龈袋中，以提供持续的HG递送。第一阶段的目标是表明，附着在微珠上的汞可以在体外抑制三种红色复合物病原体的细菌蛋白酶，并检查其对牙龈疟原虫生物膜的影响（AIM 1）。下一个目标是证明汞微头能够防止牙龈疟原虫感染后牙龈成纤维细胞的细胞死亡（AIM 2）。最后，将使用小鼠腔室模型来评估珠子上递送的汞的能力，以减少体内的牙龈毒性毒力，生存力和宿主炎症反应（AIM 3）。