New Biomarkers and Targets to Identify and Treat Corticosteroid-Resistant Asthma
NJH ID: #13-12
Glucocorticoids (GCs) are the most potent anti-inflammatory drugs used for treatment of asthma and other chronic inflammatory or autoimmune diseases. Up to 20% of asthmatics are refractory to GC therapy and are referred to as steroid resistant (SR). SR asthmatics are characterized by increased airway inflammation that cannot be inhibited by GS treatment. Given the variable responses to corticosteroid therapy in asthmatics, alternative therapeutics are needed for personalized treatment of asthma.
Endotoxin or lipopolysaccharide (LPS) exposure, a component of the outer membrane of Gram-negative bacteria, has recently been identified as an important factor that alters cellular response to CS. It has also been implicated in asthma exacerbation.
Intracellular signaling mediated by LPS/TLR4 involves binding of a series of adaptor molecules, and leads to sequential kinase phosphorylation, such as the mitogen and stress activated protein kinase 1 (MSK1) and the transforming growth factor beta associated kinase-1 (TAK-1).
Dr. Leung’s and Dr. Goleva’s laboratory identified novel biomarkers associated with asthma resistance to GC. Their lab was able to show in patient samples that elevated levels of phosphorylated MSK1 and/or phosphorylated TAK-1 correlates with resistance to corticosteroid treatment.
They also showed in an in-vitro model that treatment with a TAK-1 inhibitor was able to reverse the steroid resistance.
Diagnostics: detection levels of phosphorylated TAK-1 and/or phosphorylated MSK-1 in patient blood samples as an indication of corticosteroid resistance.
Treatment: use of TAK-1 and/or MSK-1 inhibitors to reverse steroid resistance in patients with an inflammatory disease.
State of Development
Additional patient samples are being tested to further validate the correlation of these two biomarkers with steroid resistance.
Goleva et al. Am J Resp Cr Care Med. 2013 Nov 15;188 (10):1193-201. - PMID: 24024497
International Patent Pending
Donald Y. M. Leung, MD, PhD and Elena Goleva, PhD
This technology is available for licensing.
For Further Information, Contact:
Emmanuel Hilaire, PhD
Technology Transfer Office
National Jewish Health
1400 Jackson St., Room M206b
Denver, CO 80206