June is Worldwide LAM Awareness Month which aims to raise awareness and educate people about Lymphangioleiomyomatosis (LAM). LAM is a rare disease caused by mutations in the tuberous sclerosis genes. It affects the lungs, kidneys and lymphatic system and almost exclusively affects women. Recognising the symptoms of LAM is important in order for patients to access the treatment they need early. The most common presenting symptom of LAM is worsening shortness of breath and a history of recurrent pneumothoraces. Additionally, patients can experience bloating due to fluid around their lungs and stomach (from the disruption of their lymphatic system) and angiomyolipomas, which are a type of benign tumour that can cause pain and bleeding. Although there is no cure for LAM, the progression of the disease can be slowed by a drug called Sirolimus (Rapamycin).
Due to its similarities with BHD, researchers often study both conditions. We talked to Professor Elizabeth (Lisa) Henske, Director of the Center for LAM Research and Clinical Care, Brigham and Women’s Hospital, about her work in LAM and how this translates to the BHD community. Her lab’s discovery of Tuberous Sclerosis Complex 2 (TSC2) resulted in the first FDA approved drug for LAM.
Could you tell me about your discovery of the TSC2 mutation and what that meant for patients?
LAM occurs in two forms: in women with tuberous sclerosis complex (TSC) and in women who do not have TSC (referred to as sporadic LAM). The Henske Lab discovered that sporadic LAM is caused by mutations in the TSC2 gene. A few years later, it was discovered that the TSC proteins inhibit the mTOR pathway (a pathway involved in cell growth), and Dr. Vera Krymskaya demonstrated that the mTOR pathway is hyperactive in LAM cells. Together, these discoveries paved the way for a pivotal clinical trial led by Dr. Frank McCormack, which was published in the New England Journal of Medicine in 2011. This trial proved that treatment with sirolimus (Rapamycin), an oral inhibitor of the mTOR pathway, stabilizes lung function in women with LAM. In my own clinical practice, I can see the tremendous benefit of sirolimus in so many women with LAM, allowing them to work, care for their families, travel, exercise, and live a life that is close to “normal.”
What research is currently being done into LAM?
Some of our most urgent research questions include:
1) why does LAM affect almost exclusively women?
2) can we use treatments that block estrogen’s actions to treat LAM?
3) how does the immune system promote the growth of LAM cells?
4) why do LAM cells cause cystic destruction of the lungs?
We are excited to be working with Dr. Wei Shi, a leading developmental biologist at Los Angeles Children’s Hospital, to understand how both LAM and BHD lead to cystic lung disease.
What difficulties have you come across in researching LAM?
With any rare disease, access to tissue samples (for example, lung and kidney samples) is absolutely essential to progress. We have been very fortunate that The LAM Foundation (based on Cincinnati OH) has helped make samples available for research. We are also lucky to have an exceptionally collaborative and connected LAM research community, including many dedicated scientists and physicians who are committed to curing LAM. Dr. Joel Moss, who leads the LAM program at the National Institutes of Health, has had an especially positive impact on these collaborative efforts.
From your experience what are the main differences/similarities between the symptoms of BHD and LAM?
There are important similarities and also important differences between BHD and LAM. The similarities include the risk of lung collapse (pneumothorax) and the risk of kidney tumors (renal cell carcinoma in BHD and angiomyolipomas in LAM). One important difference is that in BHD, it is unusual for shortness of breath to develop. In LAM, many women develop shortness of breath, and some become dependent on oxygen therapy, especially if the LAM is not treated early in the disease. Another difference is that LAM affects almost exclusively women, while cystic lung disease in BHD occurs in both men and women.
What can the BHD community learn from the research into LAM?
LAM research has brought together a highly collaborative group of clinicians and scientists. The scientists are diverse in their background and approaches, including biochemists, developmental biologists, cancer biologists, cell biologists, geneticists, and more. This allows LAM to be studied from many different angles. Regular scientific and clinical meetings allowing new data to be discussed and ideas to be shared have propelled LAM research breakthroughs.
What can we do to raise awareness about rare conditions such as LAM and BHD?
One of the best ways to raise awareness is to make clinically relevant discoveries. In LAM and TSC, breakthroughs have consistently boosted awareness among both scientists and clinicians. This has a “positive feedback” effect, with more awareness leading to even more progress.
The BHD Foundation sincerely thanks Professor Elizabeth (Lisa) Henske for taking part in this interview and sharing her insights on LAM and BHD. If you a researcher working on BHD we would love to hear about your research. Please contact us at firstname.lastname@example.org
To find out how you can get involved with LAM awareness month visit the LAM Foundations webpage. The LAM Foundation is a wonderful resource for both clinicians and members of the LAM community and they have several useful resources for raising awareness about LAM. Their centres of clinical excellence also support BHD patients.