Repurposing Sodium Cromoglycate For Lymphangioleiomyomatosis (LAM): An Open Label, Proof Of Concept And Feasibility Study

淋巴管平滑肌瘤病（LAM）是一种罕见的、无法治愈的女性疾病，它会导致肺部损伤，导致肺功能逐渐丧失，呼吸衰竭，有时甚至死亡。结节性硬化症复杂基因的突变导致mTOR通路（细胞生长和代谢的调节剂）的激活，进而导致“LAM细胞”的生长和存活增加，这些细胞侵入肺部并吸引其他类型的细胞在肺部形成结节，从而导致肺部损伤。抑制mTOR通路的药物可以抑制疾病活动，但需要终身使用，肺功能的丧失仍在继续，尽管比治疗前缓慢。为了完全控制疾病和预防残疾，需要针对募集细胞的额外耐受良好的长期治疗，这些治疗不依赖于mTOR激活。我们的实验室使用细胞培养和LAM的动物模型来显示LAM细胞和成纤维细胞的结节吸引肥大细胞，肥大细胞是一种通常与过敏反应相关的循环细胞。我们发现LAM结节激活这些肥大细胞，然后释放胰蛋白酶，一种导致LAM结节细胞生长的蛋白质。然后我们发现，通过使用cromoglycate钠，一种用于哮喘和过敏性疾病的药物，我们可以阻断肥大细胞中胰蛋白酶的释放，减少LAM结节的生长和肺损伤。几十年来，cromoglyate钠一直被用于哮喘治疗，长期治疗是安全的，而且价格低廉，这意味着它可以很快应用于患有LAM的女性。我们的实验室研究表明，cromoglyate钠作用于不依赖于mTOR通路激活的细胞，该药物可以单独使用，也可以与mTOR抑制剂一起使用，以减少mTOR抑制剂治疗患者肺功能的残余下降。我们计划进行一项临床试验，其中21名同时接受mTOR抑制剂治疗的LAM女性和21名未接受mTOR抑制剂治疗的LAM女性将接受cromoglyate钠吸入器治疗28周。我们将利用血管内皮生长因子- d （LAM中疾病程度和活性的蛋白质标志物）血液水平的降低来确定cromoglyate钠是否可能对LAM有帮助。这项研究将通过诺丁汉的国家LAM中心和生物医学研究中心进行，大多数英国LAM患者都接受治疗。与LAM行动，英国LAM患者慈善机构合作，我们设计了这项研究，使患者更容易参与，通过在患者的临床就诊时进行研究访问，并测试使用家庭肺功能监测技术，这意味着患者不需要额外访问中心。我们还将测量标准肺功能和生活质量。LAM是一种罕见的疾病，患有LAM的女性需要长途跋涉到LAM中心接受治疗，我们希望通过这种“患者友好”的研究设计，在临床护理以上没有研究访问，我们可以减少患者的不便，让人们更容易参与。如果cromoglyate钠看起来可能有效，我们将根据研究结果计划更大规模的研究，看看cromoglyate钠是否能减少LAM中肺功能的丧失。在本研究中，家庭肺功能监测的使用将被评估为罕见肺病试验的结果测量。

Lymphangioleiomyomatosis (LAM) is a rare, incurable, disease of women which causes lung damage leading to progressive loss of lung function, respiratory failure and sometimes death. Mutations in the tuberous sclerosis complex genes leads to activation of the mTOR pathway, a regulator of cell growth and metabolism, in turn causing increased growth and survival of 'LAM cells' which invade the lungs and attract other cell types to form nodules in the lungs which cause lung damage. Drugs that inhibit the mTOR pathway suppress disease activity but require lifelong use and lung function loss continues albeit more slowly than before treatment. To control the disease fully and prevent disability, additional well tolerated long term treatments targeting the recruited cells that are not dependent on mTOR activation are required. Our laboratory has used cell culture and animal models of LAM to show that nodules of LAM cells and fibroblasts attract mast cells, a circulating cell normally associated with the allergic response. We found that LAM nodules activate these mast cells which then release tryptase, a protein which caused the growth of cells in LAM nodules. We then showed that by using sodium cromoglycate, a drug used in asthma and allergic diseases, we could block the release of tryptase from mast cells, reducing the growth of LAM nodules and lung damage. Sodium cromoglycate has been used for decades as an asthma treatment where it has been shown to be safe in long term treatment and is inexpensive, meaning it could be quickly applied to women with LAM. As our laboratory studies show that sodium cromoglycate acts on cells that are not dependent upon activation of the mTOR pathway, the drug could be helpful both alone and when used with mTOR inhibitors to reduce the residual decline in lung function in mTOR inhibitor treated patients. We plan to perform a clinical trial in which 21 women with LAM who are also treated with an mTOR inhibitor and 21 not treated with an mTOR inhibitor will be treated with a sodium cromoglycate inhaler for 28 weeks. We will use reduction in the blood level of a protein marker of disease extent and activity in LAM, vascular endothelial growth factor-D, to determine if sodium cromoglycate may be helpful in LAM. The study will run through the National LAM Centre and Biomedical Research Centre in Nottingham where most UK LAM patients receive care. Working with LAM action, UK LAM patient charity we have designed the study to make it easier for patients to take part, by performing the reseach study visits at the patients' clinical visits and test the use of home lung function monitoring technology, meaning no extra visits to the centre will be required for patients. We will also measure standard lung function and quality of life. LAM is a rare disease and women with LAM have to travel long distances to the LAM Centre for their care, we hope by using this 'patient friendly' study design with no study visits above clinical care, we can reduce paient inconvenience and make it easy for people to participate. If sodium cromoglycate looks like it may be effective, we will use the results of the study to plan a larger study to see if sodium cromoglycate reduces the loss of lung function in LAM. The use of home lung function monitoring in this study will be evaluated as an outcome measure for rare lung disease trials.