Precision Medicine: UAB Study Creates 'Mini-lung' to Study Effect of Pulmonary Fibrosis Drugs


 
Veena Antony, MD

Pulmospheres, three dimensional multicellular spheroids composed of lung cells from individual patients, were shown to be effective in predicting the efficacy of medications for idiopathic pulmonary fibrosis, according to findings from UAB scientists presented in JCI Insight, a journal of the American Society for Clinical Investigation.

Pulmospheres are tiny spheres -- about one millimeter in diameter -- which contain all the various cell types found in a human lung and are grown from tissue obtained from a surgical lung biopsy. Pulmospheres give researchers a 3D model to study various aspects of cell biology and disease mechanisms.

"Our results suggest that pulmospheres simulate the microenvironment in the lung and serve as a personalized and predictive model for assessing responsiveness to antifibrotic drugs in patients with IPF," said Veena Antony, MD, professor in the Division of Pulmonary, Allergy and Critical Care Medicine.

The UAB research team grew pulmospheres from 20 patients with idiopathic pulmonary fibrosis and nine control patients. They then examined whether the pulmospheres reacted to one of two commonly used medications for IPF.

"There is no cure for IPF, but there are two drugs that can help slow the rate of decline," Antony said. "Not all patients respond to both drugs. We need a reliable test that can predict which drug works best for which patient."

The pulmospheres were grown to useable size in about 24 hours following the biopsy, then exposed to the two medications, pirfenidone and nintedanib. Within about 16 hours, researchers were able to observe if the spheres responded favorably to one, both or neither of the medications.


Victor Thannickal, MD

"This is a wonderful example of precision medicine," said Victor Thannickal, MD, director of the UAB Division of Pulmonary, Allergy and Critical Care Medicine. "Using pulmospheres derived from a patient's own cells may allow clinicians to tailor specific drugs to an individual patient without exposing that patient to potential side-effects or harm from treatments that are unlikely to be effective."

Of the 20 subjects enrolled in this study, three patient's pulmospheres responded only to nintedanib and the pulmospheres of four patient's responded only to pirfenidone. Eleven patient's pulmospheres responded to both drugs and two patient's pulmospheres did not respond to either drug.

Researchers confirmed the findings by following the patients over time, establishing that the response predicted by the pulmospheres was clinically observed in the patients.

Pulmospheres were developed in cancer research as a means of targeting potential drugs. A hallmark of IPF is an aggressive invasion by myofibroblasts, which mirrors the invasive phenotype of malignant cells, giving researchers reason to think that pulmospheres might work in IPF. The UAB trial was the first to study pulmospheres in IPF.

Antony also hopes that modern drug discovery techniques, using high-throughput screening technology will be enhanced by the use of pulmospheres.

"There are many potential therapeutic agents for IPF in the discovery pipeline now, and this technique might prove to be an effective way to determining which are the most promising," she said.

The UAB team consisted of Antony, Thannickal, Joao de Andrade, MD, Ranu Surolia, PhD, Fu Jun Li, MD, PhD, Zheng Wang, MC, Huashi Li, Gang Liu, MD, Yong Zhou, MD, PhD, Tracy Luckhardt, MD, Sejong Bae, PhD, Rui-ming Liu, MD, PhD, and Sunad Rangarajan, MD.

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