Sirolimus stabilizes lung function in most patients with LAM, and even appears to reduce the incidence of pneumothorax, but lung collapses still sometimes occur in patients on the drug.

Talc pleurodesis is arguably the most effective approach to prevent recurrences, but because the particle persists indefinitely in the chest, it can also be associated with complications such as chronic pain and difficulties with bleeding if thoracic surgery is required in the future.

We have therefore been interested in developing an approach to pleurodesis with a biodegradable particle that will fuse the lung to the chest wall as effectively as talc but will also be removed by the body over time.

In studying another rare lung disease called pulmonary alveolar microlithiasis, we discovered that the lung defends itself against the bone-like hydroxyapatite particles that fill the alveoli (tiny air sacs) in that disease by recruiting cells from the bloodstream and converting them into bone-dissolving osteoclasts. We reasoned that the same process would apply in the pleural space, and that hydroxyapatite particles introduced into the chest cavity after pneumothorax would cause durable pleural fusion like talc but would be removed by osteoclast action. Furthermore, hydroxyapatite is composed of nothing more than calcium and phosphate, natural substances that are readily cleared by the kidneys, so the risk for toxicity is very low.

Indeed, we found that commercially available hydroxyapatite microliths (often used in dental, orthopedic, and cosmetic procedures) protected mice from induced pneumothorax, long after the particle had been degraded by osteoclasts and without producing any safety concerns in the animals.

We decided to try to bring this therapy to the bedside and approached the LAM Foundation for funding to help us test a ‘GMP’ grade hydroxyapatite particle that is manufactured by standards appropriate for human use. The particle we chose is commercially available and FDA approved for injection into the skin for cosmetic purposes to reduce wrinkles and improve facial contours.

Gifts to The LAM Foundation supported our work to prove that the GMP hydroxyapatite particle is effective for pleurodesis in mice and paved the way for us to receive additional funding from the Falk Foundation to test the approach in an animal model with pleural membranes that more closely resemble ours, minipigs. Those experiments validated the safety and efficacy of hydroxyapatite pleurodesis in a larger animal species, as is typically necessary before human use is considered, and enabled us to receive an NIH Catalyze grant to prepare us to approach the FDA for approval to test this therapy in human trials. We are now applying for ~$1M in funding from the NIH and the Falk Foundation for additional animal toxicity studies that the FDA will require of us.

This is yet another example of how the LAM Foundation has facilitated science with the potential to favorably impact outcomes in patients suffering with this disease. The LAM Foundation was the first to the table with support to develop VEGF-D as a diagnostic biomarker to reduce the need for lung biopsy, for the MILES trial that identified sirolimus as an effective therapy (and for MILED trial designed to refine it), for the single cell RNA sequencing studies that identified the uterus as the likely source for LAM cells that invade the lung, and for the development of LAM Guidelines used to standardize LAM care across the globe. If hydroxyapatite pleurodesis becomes a new therapy for pneumothorax in patients with LAM, no small measure of the credit will be due to the LAM Foundation for stepping in at a pivotal point to maintain momentum and facilitate the cascade of funding that will be required to get this treatment to the bedside.

These are very difficult times for non-profits, and my personal plea to all LAM families is to redouble efforts to support this organization that has done so much to alleviate suffering and improve care for all patients with LAM.

Frank McCormack, M.D.

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