Summary National Jewish scientists have identified families of compounds that can increase the transport of thiol-containing molecules, like glutathione, from the cell. Cystic fibrosis and a number of inflammatory lung diseases share a diminished level of glutathione in the epithelial lining fluid and excessive lung inflammatory response. The compounds identified have shown to increase endogenous glutathione in the epithelial lining fluid and therefore could decrease oxidative damage in these diseases. Increasing glutathione efflux is also beneficial in sensitizing cancer cells to anti-cancer agents that cause oxidative damage. These discoveries form the basis of a novel drug discovery platform that modulates oxidative stress in human disease.
Treatment with these compounds in mice increased the levels of glutathione in the extracellular compartment and the lung epithelial lining fluid (ELF). Significant multidrug resistance-associated proteins-specific efflux of glutathione has also been demonstrated in cancer cell lines with a concomitant potentiation of cisplatin cytotoxicity.
Potential Applications Lung diseases, such as cystic fibrosis, chronic beryllium disease, sarcoidosis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, chronic obstructive lung diseases, idiopathic interstitial pneumonia, and diffuse fibrosing alveolitis.
Adjuvant therapeutic in radiation or chemotherapy treatment for cancer.
Advantages of Invention Many of the compounds are well known and characterized, including one that is currently approved and marketed for unrelated indications.
Compartment and tissue specific secretion of thiol-containing molecules.
An improvement over treatment with exogenous glutathione, which has a short half-life, poor bioavailability, and a lack of stability.
State of Development In mice, treatment with these compounds increased the levels of glutathione in the extracellular compartment and the lung epithelial lining fluid (ELF). Significant MRP-specific efflux of glutathione has also been demonstrated in cancer cell lines with a concomitant potentiation of cisplatin cytotoxicity.
Further R&D Required Additional in vivo studies with other animal models.
Patent Status Issued U.S. Patent #7,498,047 Published U.S. Patent Application #20060135585; International Publication #WO2004/042020; other U.S. and international patents pending.
Inventors Brian Day, PhD, Leonard Velsor, PhD and Remy Kachadourian, PhD
Licensing Status This technology is available for licensing.
For Further Information, Contact: Emmanuel Hilaire, PhD Director Technology Transfer Office National Jewish Health 1400 Jackson Street, Room M206b Denver, CO 80206 Voice: 303.398.1262 Fax: 303.270.2352 HilaireE@njhealth.org