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，妇女的疾病，造成肺损伤，导致肺功能的逐步丧失，呼吸衰竭，有时死亡。结节性硬化症复合体基因的突变导致mTOR通路的激活，mTOR通路是细胞生长和代谢的调节因子，进而导致“LAM细胞”的生长和存活增加，LAM细胞侵入肺部并吸引其他细胞类型在肺部形成结节，从而导致肺损伤。抑制mTOR通路的药物抑制疾病活动，但需要终身使用，肺功能丧失持续，尽管比治疗前慢。为了完全控制疾病并预防残疾，需要靶向不依赖于mTOR激活的募集细胞的额外的耐受性良好的长期治疗。我们的实验室已经使用细胞培养和LAM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，然后释放类胰蛋白酶，一种引起LAM结节中细胞生长的蛋白质。然后，我们发现，通过使用色甘酸钠（一种用于哮喘和过敏性疾病的药物），我们可以阻止肥大细胞释放类胰蛋白酶，减少LAM结节的生长和肺损伤。色甘酸钠已被用作哮喘治疗数十年，已被证明在长期治疗中是安全的，并且价格低廉，这意味着它可以快速应用于LAM女性。由于我们的实验室研究表明，色甘酸钠作用于不依赖于mTOR通路激活的细胞，该药物单独使用和与mTOR抑制剂一起使用时都有助于减少mTOR抑制剂治疗患者的肺功能残留下降。我们计划进行一项临床试验，其中21名也接受mTOR抑制剂治疗的LAM女性和21名未接受mTOR抑制剂治疗的LAM女性将接受色甘酸钠吸入剂治疗28周。我们将使用LAM中疾病程度和活性的蛋白质标记物血管内皮生长因子-D的血液水平的降低来确定色甘酸钠是否对LAM有帮助。这项研究将通过位于诺丁汉的国家LAM中心和生物医学研究中心进行，大多数英国LAM患者都在那里接受治疗。与英国LAM患者慈善机构LAM action合作，我们设计了这项研究，通过在患者临床访视时进行研究访问并测试家庭肺功能监测技术的使用，使患者更容易参与，这意味着患者无需额外访问该中心。我们还将测量标准肺功能和生活质量。LAM是一种罕见疾病，患有LAM的女性必须长途跋涉到LAM中心接受治疗，我们希望通过使用这种“患者友好型”研究设计，在临床治疗之上没有研究访视，我们可以减少患者的不便，使人们更容易参与。如果色甘酸钠看起来可能有效，我们将利用研究结果计划一项更大的研究，看看色甘酸钠是否能减少LAM患者的肺功能丧失。本研究中家庭肺功能监测的使用将作为罕见肺病试验的结局指标进行评价。

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.