Novel lipid -based therapies for cystic fibrosis

描述(申请人提供)：尽管囊性纤维化(一种致命性常染色体疾病)的遗传原因已经知道十多年了，但仍然缺乏有效的治疗方法。肺部疾病仍然是CF发病率和死亡率的主要原因。慢性阻塞性肺疾病的特点是炎症和慢性感染的失调，最终结果是进行性的支气管扩张对呼吸道的破坏。慢性阻塞性肺疾病的气道炎性反应是持续的中性粒细胞；反过来，激活的中性粒细胞的产物似乎在很大程度上导致了气道的破坏。尽管近几十年来CF治疗取得了进展，但肺功能仍然不可避免地下降，最终导致死亡或需要肺移植。因此，迫切需要一种有效、安全的方法来抑制CF中异常的呼吸道炎症反应。 我们已经发现，某些内源性脂质介质的水平在具有良好特征的CFs呼吸道炎症和感染的小鼠模型中具有有益的影响。这些数据表明，这些基于脂质的介体在CF中具有治疗潜力。 该计划的最终目标是在这些发现的基础上开发一种基于脂质的CF治疗方法。我们的目标是通过：(1)确认和扩展我们的初步数据，表明使用适当的脂质衍生物对与CF相关的慢性感染和炎症的小鼠模型有治疗作用，以及(2)设计和合成改进的脂质类似物，并测试选定类似物扩大规模的可行性，以用于临床前评估和进一步研究，从而验证治疗CF肺部炎症的可行性和可行性。如果成功，这些研究将为在这一领域进行临床前和临床研究提供基础。

DESCRIPTION (provided by applicant): Although the genetic cause of cystic fibrosis (CF), a lethal autosomal disorder, has been known for over a decade, an effective therapeutic method is still lacking. Pulmonary disease remains the major cause of morbidity and mortality in CF. The CF lung is marked by dysregulated inflammation and chronic infection, the end result being progressive bronchiectatic destruction of the airways. The airway inflammatory response in CF is persistently neutrophilic; in turn, products of activated neutrophils appear to be largely responsible for airway destruction. Despite progress in CF therapy in recent decades, the norm is still an inexorable decline in pulmonary function, leading eventually to death or to a need for lung transplantation. There is thus a pressing need for an effective, safe method for suppressing aberrant airway inflammatory responses in CF. We have found that levels of certain endogenous lipid mediators have beneficial effects in a well-characterized mouse model of the airway inflammation and infection of CF. These data suggest that such lipid-based mediators have therapeutic potential in CF. The ultimate goal of this program is to develop a lipid-based therapy for CF, based on these findings. We aim to validate the viability and feasibility of treating pulmonary inflammation in CF by: (1) confirming and extending our preliminary data indicating therapeutic benefit in mouse models of CF-related chronic infection and inflammation using appropriate lipid derivatives, and (2) designing and synthesizing improved lipid analogues and testing the feasibility of scale-up of selected analogues for preclinical evaluation and further studies. If successful, these studies will provide the basis for pursuing preclinical and clinical studies in this area.