Antimicrobial Phototherapy of Antibiotic Resistant Chronic Sinusitis

描述（由申请人提供）：该研究项目将在体外新型解剖学精确的人类上颌窦CRS多微生物生物膜模型和离体活体人类呼吸纤毛粘膜模型中验证慢性复发性鼻窦炎（CRS）治疗的原理、安全性和确定最佳亚甲基蓝(MB)/EDTA药物和光照参数。这些结果以及我们已经开发的一次性鼻窦照明系统将立即转化为CRS治疗的人体临床试验，并可能导致这种急需的治疗方法的快速采用和商业化。CRS是美国最常见的慢性疾病之一，影响了大约3700万美国人。此外，据估计，紧急救援服务每年带来1800 - 2200万次办公室访问，每年超过50万次紧急访问，导致大约7300万限制活动日，每年的总费用为60亿美元。在临床实践中，尽管鼻窦内窥镜手术、过敏治疗和培养指导长期口服、局部或静脉抗生素治疗，仍有相当一部分CRS患者对治愈有耐药性。许多研究报告了耐药的铜绿假单胞菌、流感嗜血杆菌、肺炎链球菌和金黄色葡萄球菌生物膜在耐药CRS的鼻窦中存在。众所周知，微生物生物膜，包括CRS生物膜，对标准抗生素治疗和宿主免疫防御机制具有耐药性，因此导致CRS治愈率低，并增加了抗生素耐药性。由于标准治疗方法无法控制和治愈CRS，因此对临床有效、无创、无毒、成本效益高、可重复、无痛且不会导致抗生素耐药性的CRS局部非抗生素治疗方式的需求尚未得到满足。基于MB的抗菌光动力疗法（aPDT）具有快速采用治疗和快速商业化的优势，具有成功实现这些目标的巨大潜力。这项拨款提案将确定最佳的MB药物和光参数，以便在一种新的解剖学精确的上颌窦模型中有效治疗人类CRS多微生物生物膜。此外，将对aPDT治疗的活体人呼吸道纤毛粘膜进行组织病理学分析，以证明aPDT治疗上颌窦粘膜的安全性。虽然MB aPDT已被证明在体外有效根除生物膜，但这些研究将代表已知的首次在离体模型中对MB aPDT进行系统研究，包括评估治疗的有效性和治疗的安全性，治疗的生物膜定植于人鼻窦呼吸纤毛粘膜。从这项研究中确定的最佳治疗参数随后计划直接转化为治疗CRS的人体临床试验。在更广泛的全球层面上，控制感染的非抗生素疗法的好处将被视为一项革命性的医学进步，可用于广泛的医疗应用，并将对全世界数百万人的生活质量产生积极影响。

DESCRIPTION (provided by applicant):This research project will demonstrate proof of principle, safety and determine the optimal methylene blue (MB)/EDTA drug and light parameters necessary for chronic recurrent sinusitis (CRS) treatment in an in vitro novel anatomically accurate human maxillary sinus CRS polymicrobial biofilm model and in an ex vivo live human respiratory ciliated mucosa model. These results along with our already developed disposable sinus illumination system will be immediately translatable to a human clinical trial for CRS treatment and may result in the rapid adoption and commercialization of this much needed therapy. CRS is one of the most common chronic conditions in the United States affecting an estimated 37 million Americans. It is also estimated that CRS results in 18-22 million office visits per year and over 500,000 emergency visits per year resulting in an estimated 73 million restricted activity days with an aggregated cost of six billion dollars annually. In clinical practice there is a significant subpopulation of patients with CRS who remain resistant to cure despite endoscopic sinus surgery, allergy therapy and culture directed long term oral, topical or intravenous antibiotic therapy. Numerous studies have reported the presence of antibiotic resistant Pseudomonas aerugenosa, Hemophilus influenza, Streptococcus pneumoniae and Staphylococcus aureus biofilms in the sinuses of cure resistant CRS. Microbial biofilms, including CRS biofilms, are notoriously resistant to standard antibiotic therapy as well as host immunologic defense mechanisms therefore contributing to the dismal cure rates of CRS and to increased antibiotic resistance. Due to the failure of standard therapies to control and cure CRS, there is an unmet medical need for an alternative clinically effective, non- invasive, non-toxic, cost-effective, repeatable, painless topical non-antibiotic treatment modality for CRS that does not result in antibiotic resistance. MB based antimicrobial photodynamic therapy (aPDT) has the significant potential to successfully achieve these goals with the advantages of rapid adoption of the therapy as well as rapid commercialization. This grant proposal will determine the optimal MB drug and light parameters necessary to effectively treat human CRS polymicrobial biofilms in a novel anatomically accurate maxillary sinus model. In addition, histopathological analysis will be performed on the aPDT treated live human respiratory ciliated mucosa to demonstrate the safety of aPDT on maxillary sinus mucosa. Although MB aPDT has been demonstrated to be effective in eradicating biofilms in vitro, these studies will represent the first known systematic studies of MB aPDT in an ex-vivo model, including evaluating the effectiveness of the therapy and safety of the therapy, on biofilm colonized human respiratory ciliated mucosa as is found in the human paranasal sinuses. The optimal treatment parameters determined from this study are then planned to be directly translated to a human clinical trial for the treatment of CRS. On a more global level, the benefit of a non-antibiotic therapy for infection control would be considered a revolutionary medical advancement that could be used in wide ranging medical applications and would positively affect the quality of life for millions of people worldwide. PUBLIC HEALTH RELEVANCE: Chronic recurrent sinusitis (CRS) is one of the most common diseases in the United States. It is estimated that CRS results in 18-22 million office visits per year, 73 million restricted activity days and an aggregated cost of $6 Billion annually. In clinical practice there is a significant subpopulation of patients with CRS who remain resistant to cure despite endoscopic sinus surgery, allergy therapy and culture directed long term oral, topical or intravenous antibiotic therapy. Due to the failure of standard therapies to control and cure CRS, other novel non-antibiotic therapies are desperately needed that are able to destroy or control biofilms and antibiotic resistant bacteria. Developing such a therapy is the specific objective of this research and development effort. MB based antimicrobial photodynamic therapy (aPDT) has the significant potential to successfully achieve these goals with the advantages of rapid adoption of the therapy as well as rapid commercialization. This grant proposal will determine the optimal MB drug and light parameters for safe and effective CRS treatment in an in vitro novel anatomically accurate human maxillary sinus CRS polymicrobial biofilm model and in an ex vivo live human respiratory ciliated mucosa model, the results of which will be directly translated to a human clinical trial for the treatment of CRS.