Glycosaminoglycans to Treat and Prevent Radiation-Induced Oral Mucositis

项目总结/摘要 口腔粘膜炎是一种非常痛苦的炎症性疾病，经常在癌症治疗过程中发生 影响了五十万美国人伴随的疼痛是如此严重，病人往往需要麻醉剂 止痛药临床表现为口腔和胃肠道溃疡， 会因机会性感染而恶化许多患者还患有口干，导致难以进行治疗。 因为唾液腺功能下降而吞咽。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， 每名病人额外支付一万七千至四万元。预防口腔粘膜炎会大大提高癌症 治疗以及患者的健康。GlycoMira的主要候选药物GM-1111是一类新的抗- 当通过每日一次给药时调节过度活跃的先天免疫系统的炎性药物 皮下注射SBIR I期和II期研究结果证明了其在减少 放射性口腔粘膜炎模型中疾病的严重程度和发生率：GM-1111降低 组织溃疡和舌头发炎。在组织学上，GM-1111处理组的口腔组织 显示上皮损伤明显减轻，伴有轻度白细胞浸润，粘膜层增厚 以及与来自载体处理的对照的组织相比防止粘液腺改变。 病变组织的生化和基因表达分析显示Toll样蛋白表达增加。 受体，NLRP 3炎性体以及它们的下游促炎细胞因子，所有这些都是 GM-1111处理降低。总的来说，数据表明GM-1111有很大的潜力减少 人类口腔粘膜炎。GlycoMira还生产符合cGMP的GM-1111，并生产其 制造规格。为了进一步开发商业上可行的口腔粘膜炎治疗药物，我们 向FDA提出用于临床试验的研究性新药（IND）申请。 目的是（1）描述GM-1111在非临床研究中的安全性特征，以及（2）生产 临床试验准备无菌制剂（无菌灌装/包装和贴标/包装）并检测其稳定性。的 该研究成果将通过IND申请将药物开发推向临床阶段 并推动该药物的商业化，以帮助患有这种毁灭性疾病的患者。

Project Summary/Abstract Oral mucositis is a devastatingly painful inflammatory disease that frequently develops during cancer therapy and affects half a million Americans. 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 greatly enhance the cancer therapy as well as the wellness of the patients. GlycoMira's lead candidate, GM-1111, is a new class of anti- inflammatory drugs that modulate an overactive innate immune system when administered via once daily subcutaneous injection. The SBIR Phase I and II study results demonstrate its powerful efficacy in reducing the severity and the occurrence of the disease in radiation-induced oral mucositis models: GM-1111 reduced tissue ulceration and inflammation in the tongue. Histologically, oral tissues from the GM-1111 treated group showed markedly reduced damages in the epithelium with mild infiltration of leukocytes, thicker mucosal layers and prevention of mucous glandular alterations compared to the tissues from vehicle treated controls. Biochemical and gene expression analyses of the diseased tissues revealed increased expression of Toll-like receptors, NLRP3 inflammasome as well as their downstream pro-inflammatory cytokines all of which were reduced with GM-1111 treatment. Overall, the data suggest that GM-1111 has substantial potential to reduce oral mucositis in humans. GlycoMira also manufactured cGMP compliant GM-1111 and generated its manufacturing specifications. To further develop a commercially viable therapeutic for oral mucositis, we propose studies that will be used for the Investigative New Drug (IND) application to the FDA for clinical trials. The objectives are to (1) delineate the safety profiles of GM-1111 in nonclinical studies and (2) manufacture clinical trial ready sterile drug product (aseptic fill/finish and labeling/packaging) and test its stability. The results of the proposed research will lead the drug development to the clinical stage through IND application and propel the commercialization of the drug to the patients suffering from this devastating disease.