New research out of the Perelman School of Medicine finds that a deleted gene may be responsible for activating the signaling pathway for lymphangioleiomyomatosis (LAM), and targeting the pathways may be a way to treat LAM, according to a study published in the latest issue of Nature Communications.
LAM, a rare pulmonary disease that predominantly affects women of child-bearing age and is exacerbated by pregnancies, is a cancer-like disease that leads to cysts developing in the lungs, respiratory failure, and increasingly severe and potentially fatal complications. Sirolimus (rapamycin) is the first, and only, treatment approved by the FDA for the treatment of LAM. However, this drug is not effective or well tolerated by some LAM patients, and declining lung function has been shown to continue after treatment. Therefore, there is an urgent unmet clinical need for new LAM therapies.
After single cell RNA sequencing of a human LAM lung and comparing that to an age and sex match of a control lung, Penn researchers, led by senior author Vera P. Krymskaya, a professor of medicine at Penn, who has studied LAM disease for the last two decades, and first author Kseniya Obraztsova, a postdoctoral researcher in pulmonary, allergy, and critical care, found a unique cellular appearance of LAM cells that had no equivalent in the control lungs. By deleting the TSC2 gene in an animal model, the researchers found age- and sex-linked structural and functional lung decline, exacerbated by pregnancies. These lung cells also exhibited increased activation of the WNT signaling pathway. The researchers found that while targeting the WNT pathway alone may not be effective in LAM disease, a combination therapy inhibiting this pathway and knocking out or impairing other mechanisms could be a potentially successful treatment.
“The cellular cause of LAM is likely a complex relationship between subsets of lung cells affected by TSC2-deficient LAM cells,” says Krymskaya. “Nevertheless, our research has shown that targeting drugs against proteins in the WNT pathway may provide new ways to treat LAM patients.”
This story is by Alex Gardner. Read more at Penn Medicine News.