Research ArticlePulmonary Lymphangioleiomyomatosis

Prevention of Alveolar Destruction and Airspace Enlargement in a Mouse Model of Pulmonary Lymphangioleiomyomatosis (LAM)

Science Translational Medicine  03 Oct 2012:
Vol. 4, Issue 154, pp. 154ra134
DOI: 10.1126/scitranslmed.3003840

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On the LAM, in Search of Treatments

Typically diagnosed in women of childbearing age or in patients with tuberous sclerosis (a genetic disease associated with nonmalignant tumors in the brain and other organs), pulmonary lymphangioleiomyomatosis (LAM) is a rare disease that results in proliferation of smooth muscle–like cells in the lung and destruction of the surrounding normal lung tissue, leading to progressive respiratory problems. LAM can also cause benign tumors in other organs such as the kidneys. Although antiestrogen medications have been used to treat this disorder, these drugs have major side effects and have to be used indefinitely because they do not cure the disease. Now, Goncharova and colleagues have developed a mouse model that recapitulates the key clinical features of LAM and shows promising results after treatment with a combination of medications.

Even in patients who do not have tuberous sclerosis, LAM is associated with inactivating mutations in tuberous sclerosis complex (TSC) genes, which encode tumor suppressor proteins. The authors found that injection of kidney tumor cells derived from mice lacking one of these genes, TSC2, into nude mice produced symptoms that are similar to those seen in human LAM disease. These mice developed LAM-like lung lesions, which accumulated around blood vessels and airways, as well as inflammation and destruction of surrounding normal lung tissue. Using this mouse model, the authors demonstrated that simvastatin (a commonly used cholesterol-lowering drug) and rapamycin (an immunosuppressive medication) displayed an additive effect on LAM lesions, inhibiting their growth. In addition, the authors showed that simvastatin decreased the destruction of normal lung tissue, which rapamycin alone did not do.

The rapamycin-simvastatin treatment combination did not cure LAM in the mice, and more research is needed to determine whether these promising findings will translate to human patients. However, the two drugs are already approved for use in human subjects for other indications. Thus, the current study brings this treatment regimen one step closer to the clinic—and to a more tolerable long-term therapy for LAM.