Glycosaminoglycans to Treat and Prevent Radiation-Induced Oral Mucositis

糖胺聚糖治疗和预防放射性口腔粘膜炎

• 批准号: 9333339
• 负责人: Won Yong Lee
• 金额: $ 38.14万
• 依托单位: GLYCOMIRA, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333339
• 关键词: Acute; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Biochemical; Blocking Antibodies; Cancer Patient; Cathepsins; Cell Death; Cell Death Signaling Process; Cells; Clinical; Complex; Cytoprotective Agent; Data; Deglutition; Development; Disease; Dose; Enteral Feeding; Enzymes; Epithelial Cells; Event; FDA approved; Feasibility Studies; Formulation; Frequencies; Gastrointestinal tract structure; Glycosaminoglycans; Hamsters; Head and Neck Cancer; Histologic; Human; Infiltration; Inflammation; Inflammatory; Innate Immune System; Interruption; Lead; Leukocytes; Measures; Mediating; Medicine; Modeling; Molecular; Molecular Target; Mucositis; Mucous body substance; Mus; Narcotics; Necrosis; Nerve Growth Factors; Opportunistic Infections; Oral; Oral Ulcer; Oral cavity; Oral mucous membrane structure; Pain; Pathway interactions; Patients; Phagocytosis; Pharmaceutical Preparations; Phase; Physicians; Prevention; Process; Quality of life; Radiation; Radiation induced damage; Radiation therapy; Regimen; Research; Roentgen Rays; Safety; Salivary Glands; Schedule; Signal Pathway; Signal Transduction; Signaling Molecule; Small Business Innovation Research Grant; TLR2 gene; TLR4 gene; Testing; Thick; Tissues; Tongue; Topical application; Transplantation; Ulcer; Xerostomia; base; cancer cell; cancer complication; cancer therapy; cell injury; chemoradiation; cost; cytotoxic; effective therapy; experimental study; insight; irradiation; neoplastic cell; oral mucositis; outcome forecast; phase 1 study; prevent; protective effect; repaired; therapy development; treatment group; tumor

ABSTRACT Oral mucositis is a devastatingly painful inflammatory disease that frequently develops during cancer therapy and affects half a million people in the US. The accompanying pain is so severe that patients often require narcotic pain medicines. The clinical manifestations are ulcers in the mouth and gastrointestinal tract, which are exacerbated by opportunistic infections. Many patients also suffer from dry mouth causing difficulty in swallowing because of the decreased salivary gland function. As a result, these patients often need feeding tubes which interrupts their cancer treatment. The financial burden to the patient is staggeringly high costing an additional $17,000 to $40,000 for each patient. Preventing oral mucositis will therefore greatly enhance the cancer therapy as well as the wellness of the patients. GlycoMira's lead candidate, GM-0111, is a new class of anti-inflammatory drugs. The SBIR Phase I study results demonstrate its powerful anti-inflammatory effects in a radiation-induced oral mucositis animal model: GM-0111 reduced tissue ulceration and inflammation in the tongue. Histologically, tongue tissues from the GM-0111 treated group showed markedly reduced infiltration of leukocytes with thicker mucosal layers and prevention of mucous glandular alterations compared to the tissues from vehicle treated animals. Biochemical analyses also showed consistently lower leukocyte enzyme MPO activity as well as reduced concentration of nerve growth factor (NGF) in GM-0111 treatment groups. In addition, GM-0111 treatment prevented radiation-induced alterations of the salivary glands. Overall, the data suggest that it is feasible to use GM-0111 to prevent oral mucositis. The current SBIR Phase II application proposes to further develop GM-0111 as a viable and effective therapy for oral mucositis. The objectives are to (1) investigate the optimal dosing regimen in a radiation-induced oral mucositis animal model, (2) determine the optimal formulation for topical delivery of GM-0111 in the oral mucosa, (3) validate the topical GM-0111 formulation in radiation and chemoradiation-induced animal models, and (4) investigate the molecular targets of GM-0111 to reduce oral mucositis. The results of the proposed research will lead to the delivery of a viable and effective therapy to the patients suffering from this devastating disease.

摘要 口腔粘膜炎是一种非常痛苦的炎症性疾病，经常在癌症期间发展 在美国有50万人受到影响。伴随的疼痛是如此严重， 需要麻醉止痛药临床表现为口腔和胃肠道溃疡， 机会性感染会加重病情许多患者还患有口干导致的困难 因为唾液腺功能下降导致吞咽困难。因此，这些患者经常需要进食 从而中断癌症治疗。病人的经济负担高得惊人， 每名病人额外支付17，000至40，000元。因此，预防口腔粘膜炎将大大提高 癌症治疗以及患者的健康。GlycoMira的主要候选人GM-0111是一类新的 消炎药。SBIR I期研究结果证明了其强大的抗炎作用， 放射诱导的口腔粘膜炎动物模型：GM-0111减少了组织溃疡和炎症， 舌头.在组织学上，GM-0111治疗组的舌组织显示出显著减少的 与组织相比，具有更厚粘膜层的白细胞和防止粘液腺改变 从媒介物处理的动物。生化分析还显示，白细胞酶MPO持续降低 活性以及神经生长因子（NGF）浓度降低。在 此外，GM-0111处理防止了放射诱导的唾液腺改变。总体而言，数据 提示GM-0111预防口腔粘膜炎是可行。目前的SBIR第二阶段应用 提出进一步开发GM-0111作为口腔粘膜炎的可行且有效的治疗。其目标是 (1)研究放射诱导的口腔粘膜炎动物模型中的最佳给药方案，（2）确定 GM-0111口腔黏膜局部给药的最佳处方;（3）验证GM-0111口腔黏膜局部给药的有效性 在放射和化学放射诱导的动物模型中的制剂，和（4）研究分子靶点 GM-0111，以减少口腔粘膜炎。拟议研究的结果将导致交付一个可行的 和有效的治疗方法。