“Sweet-P”: Molecule for Targeting Human Glucocorticoid Receptor Beta in Asthma and Cancer

Project ID: D2016-49

Background:

Despite many breakthrough innovations occurring in the $14 billion Asthma market, numerous people are still affected by fatal asthma, and the United States contains the largest population affected by severe asthma. Glucocorticoids (GCs) are the most effective and commonly prescribed anti-inflammatory agents in treating asthma. In humans, GC resistance has been documented by two major mechanisms: loss-of-function mutations in glucocorticoid receptor α (GRα) that binds GCs, or by increased expression of glucocorticoid receptor β (GRβ) that does not bind GCs, which acts as a dominant-negative inhibitor of GRα. Although GRα mutations result in GC resistance that is systemic and severe, these mutations are rare. In contrast, GC resistance based on GRβ is more common and tissue-specific in nature. Fatal asthma has been shown to express extremely high levels of GRβ in both large and small airways of the affected people. Ascending levels of GRβ in asthma patients result in GC resistance that can verge on a complete loss of drug response. These maladies have brought the need for the development of an anti-GRβ molecule that may serve as a new therapeutic for (GRβ) related diseases, especially GC-insensitive asthmatic patients.

Inventions Description:

Researchers at the University of Toledo have developed the first (and only) anti-GRβ molecule called Sweet-P that targets the GRβ gene known to cause growth, proliferation, migration, and GC hormonal therapy resistance. Sweet-P was designed as a peptide nucleic acid (PNA), conjugated to the Trans-Activator of Transcription (TAT) protein from HIV (for cellular delivery) to specifically target the 3’ untranslated region (3’ UTR) of human GRβ. Sweet-P functions by specifically binding to the 3’UTR of human GRβ and blocking microRNA-144 (miR-144), which increases expression. Sweet-P does not affect GRα levels but explicitly suppresses GRβ increasing the responsiveness to GCs. Sweet-P serves great for reversing GC-resistant diseases. Sweet-P may also be used as a treatment option for several different carcinomas where GRβ is highly expressed, including bladder, prostate, lung, or glioblastoma, as well as for liquid tumors such as in leukemia. Thus, Sweet-P is beneficial for asthma and cancer therapies.

Applications:

IP Status:  United States Patent 10457947