NJH ID: #11-06
It is estimated that 50 million people in North America are affected by allergic conditions with an associated cost of more than $10 billion dollars yearly.
The most common form of allergy, allergic rhinitis (nasal allergies), affects about 35 million Americans, 6 million of whom are children. The number of cases of asthma has doubled over the last 20 years affecting 15 million Americans, 5 million of whom are children. Even greater proportionate increases have been seen in atopic dermatitis and food allergy.
Several antagonistic drugs are used to block the action of allergic mediators, or to prevent activation of cells and degranulation processes. These include antihistamines, glucocorticoids, and theophylline. Anti-leukotrienes, such as Montelukast (Singulair) for example, are FDA approved for treatment of allergic diseases. Anti-cholinergics, decongestants, mast cell stabilizers, thought to impair eosinophil chemotaxis, are also commonly used. Although these drugs help to alleviate the symptoms of allergy, they play a limited role in chronic treatment of allergic disorders.
Runt-related transcription factors (Runx) are a novel family of transcription factors which are regulators of lineage-specific gene expression. The data suggest that Runx3 plays a critical role in regulating T-cell development, the differentiation of Th1/Th2 cells and Th1/Th2 cytokine production, and the development of an allergic disease.
Dr. Gelfand’s laboratory at National Jewish Health has shown that the proto-oncogene serine/threonine-protein kinase (PIM-1) increases upon allergen sensitization and is responsible for the downregulation of Runx3. They have shown in mouse models of peanut allergy and also asthma that inhibiting PIM-1 kinase upregulates Runx3.
This strategy substantially reduced allergic responses in mice. Therefore, upregulating Runx3 by targeting PIM-1 kinase represents a novel approach for treating allergic diseases. Scientists at National Jewish Health and the Colorado Center for Drug Discovery for have also developed novel PIM-1 kinase inhibitors because existing ones suffer from a lack of specificity and problems associated with distribution, metabolism and excretion.
Treatment of allergic disease by inhibiting PIM-1 kinase or by upregulating/sustaining the expression of Runx3.
Shin, Yoo Seob, Katsuyuki Takeda, Yoshiki Shiraishi, Yi Jia, Meiqin Wang, Leila Jackson, A. Dale Wright, Laura Carter, John Robinson, Erik Hicken, and Erwin W. Gelfand. "Inhibition of Pim1 Kinase Activation Attenuates Allergen-Induced Airway Hyperresponsiveness and Inflammation." American Journal of Respiratory Cell and Molecular Biology 46.4 (2012): 488-97. PMID: 22074702
Wang, Meiqin, Masakazu Okamoto, Joanne Domenico, Junyan Han, Shigeru Ashino, Yoo Seob Shin, and Erwin W. Gelfand. "Inhibition of Pim1 Kinase Prevents Peanut Allergy by Enhancing Runx3 Expression and Suppressing TH2 and TH17 T-cell Differentiation." Journal of Allergy and Clinical Immunology 130.4 (2012): 932-44.e12. PMID: 22944483
Gelfand, Erwin W., and Meiqin Wang. "Targeting Pim1 kinase in the treatment of peanut allergy." National Center for Biotechnology Information. U.S. National Library of Medicine, 02 Feb. 2014. PMID: 24266874
Erwin Gelfand, MD and Meiquin Wang, MD, Ph.D.
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