Background Corticosteroids (GCs) are an effective treatment for inflammation and are frequently used to treat asthma. Most patients can use this potent anti-inflammatory medication for years. However, tissue GC resistance is a well-known manifestation of chronic inflammatory disease and about 20% of patients with this treatment modality will develop resistance and become refractory to treatment.
These patients will suffer severe and uncontrolled asthma with several exacerbations a year, which accounts for 60% of the total asthma cost. Some of these severe and poorly controlled patients benefit from biologics such as Omalizumab, Mepolizumab, Reslizumab, Benralizumab or Dupilumab, but 30-50% of these patients do not respond to them. Hence, there is an unmet need for new therapeutic agents that benefit-steroid resistant asthma.
The exact mechanism of steroid resistance is poorly understood, but it has been shown that BAL type 2 innate lymphoid cells (ILC2s) from asthmatic patients are steroid resistant in a TSLP-dependent manner.
Chromobox homolog 7 (CBX7) is a chromobox domain-containing protein in the ICL2 cell nucleus that belongs to the polycomb repressor complex 1 (PRC1). CBX7 also interacts with TSLP-induced MEK2.
Use of CBX7 and/or MEK2 inhibitors to treat steroid resistant asthma
Potential Applications Diagnostics: By analyzing the increase expression levels of CBX7 or MEK2 in biological samples from patients
Treatment: treat GC resistance by administering compounds that decreases CBX7 or MEK2 activity.
State of Development In ILC2 cells isolated from blood or BAL asthmatic patients or from human lungs rejected transplants, Dr. Alam has shown that the genes for CBX7, MEK2 and TLRP were not sensitive to dexamethasone (Dex). In refractory asthma patients, ILC2 expression of CBX7 and MEK2 is increased and production of IL5 and IL13 was resistant to Dex. This resistance in ILC2 cells is reversed when treaded with an inhibitor of MEK2 (Trametinib) or CBX7 (MS37452).
In further support of the role of CBX7 in steroid resistance, it was shown that genetic deletion of CBX7 (CBX7-/-) prevents development of airway hyperreactivity and eosinophilic inflammation in a mouse model of allergic asthma. Comparable effects can be seen in Rag1-/- mice (lack T and B cells but have ILCs) treated with the CBX7 inhibitor MS37452. Dr. Alam’s laboratory is currently working on developing a steroid-resistant model of asthma in mice and will be testing the efficacy of the CBX7 inhibitor
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 HilaireE@njhealth.org