GABAA receptor modulators for the treatment of bronchoconstrictive diseases

This technology describes GABAA receptor modulators that both relax airway smooth muscle and attenuate inflammation to treat bronchoconstrictive diseases.

Unmet Need:  Therapeutics that rapidly treat bronchoconstriction with reduced side effects

Current therapeutics for bronchoconstrictive diseases, such as asthma and chronic obstructive pulmonary disease, are largely centered on beta-adrenergic agonists and corticosteroids. While often quite effective, these therapeutics suffer from serious side effects and may take weeks to reach peak efficacy. As such, therapeutics that treat bronchoconstriction through alternative pathways may replace or augment treatment of patients who are not responsive to current therapies.

The Technology: GABAA receptor modulators provide an alternative pathway to treat bronchoconstriction

This technology describes compounds that target gamma-aminobutyric acid subtype A (GABAA) receptors with high specificity to relax airway smooth muscle and attenuate inflammation. These compounds specifically target the alpha-4 and alpha-5 GABAA subunits, which were demonstrated to be the only GABAA subunits expressed in human airway smooth muscle. In contrast to current corticosteroid-based therapies, therapeutics that target the GABAA receptors may carry reduced side effects and could be administered through variable routes. In sum, this technology describes a method for treating bronchoconstrictive diseases with fewer side effects that may replace or augment current therapies.

This technology has been demonstrated to selectively relax human airway muscle cells ex-vivo.

Applications:

• Asthma treatment
• Reducing lung inflammation
• Treatment for chronic obstructive pulmonary disease
• Treatment of other bronchoconstrictive diseases

Advantages:

• Selective for specific GABAA receptor subunits
• Reduced potential for CNS effects
• Fewer side effects compared to corticosteroids
• Multiple delivery routes
• Reduces inflammation and relaxes smooth muscle in the lung

Lead Inventor:

Charles W. Emala, M.D.

Patent Information:

Patent Pending (US 20150232473)

Related Publications:

• Forkuo GS, Guthrie ML, Yuan NY, Nieman AN, Kodali R, Jahan R, Stephen MR, Yocum GT, Treven M, Poe MM, Li G, Yu OB, Hartzler BD, Zahn NM, Ernst M, Emala CW, Stafford DC, Cook JM, Arnold LA. “Development of GABAA Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments” Mol Pharm. 2016 Jun 6; 13(6): 2026-38.

• Yocum GT, Gallos G, Zhang Y, Jahan R, Stephen MR, Varagic Z, Puthenkalam R, Ernst M, Cook JM, Emala CW. “Targeting the γ-Aminobutyric Acid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction” Am J Respir Cell Mol Biol. 2016 Apr; 54(4): 546-53.

• Gallos G, Yocum GT, Siviski ME, Yim PD, Fu XW, Poe MM, Cook JM, Harrison N, Perez-Zoghbi J, Emala CW Sr. “Selective targeting of the α5-subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling” Am J Physiol Lung Cell Mol Physiol. 2015 May 1; 308(9): L931-42.

• Gallos G, Yim P, Chang S, Zhang Y, Xu D, Cook JM, Gerthoffer WT, Emala CW Sr. “Targeting the restricted α-subunit repertoire of airway smooth muscle GABAA receptors augments airway smooth muscle relaxation” Am J Physiol Lung Cell Mol Physiol. 2012 Jan 15; 302(2): L248-56.

Tech Ventures Reference:

• IR CU13064

• Licensing Contact: Sara Gusik