Modulating the Transport of Thiol-Containing Molecules for the Treatment of Lung Disease and Cancer

Tech ID: 02-16

Summary -National Jewish Health scientists have identified families of compounds that can increase the transport of thiol-containing molecules, like glutathione, from the cell.  Glutathione is a critical thiol used by a large number of repair and detoxification pathways, particularly in the lung.  Cystic fibrosis and a number of inflammatory lung diseases share a diminished level of glutathione in the epithelial lining fluid and excessive lung inflammatory responses.  The compounds identified 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, which are characterized by increased intracellular levels of glutathione and increased levels of multidrug resistance-associated proteins (MRPs) that transport glutathione, 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.

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. 

Patent - Published U.S. Patent Application # 20040087527 and # 20060135585 ; International Publication # WO 2004/042020; other U.S. and international patents pending.

Publications

  • Velsor LW, van Heeckeren A, and Day BJ. Antioxidant imbalance in the lungs of cystic fibrosis transmembrane conductance regulator protein mutant mice. Am J Physiol Lung Cell Mol Physiol 281:L31-L38, 2001.
  • Day BJ, van Heeckeren AM, Min E, Velsor LW. Role for cystic fibrosis transmembrane conductance regulator protein in a glutathione response to bronchopulmonary pseudomonas infection. Infect Immun. 2004 Apr;72(4):2045- 51.
  • Kachadourian et al. Free Rad Bio & Med 2006; 41:65-76

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
Licensing Associaate
Intellectual Property and Technology Commercialization Program
National Jewish Health
1400 Jackson Street, Room M206a
Denver, CO 80206
Voice: (303) 398-1053
Fax: (303) 270-2352
hilairee@njc.org

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