Asthma

Research Team:

UWM:  Alexander (Leggy) Arnold, Douglas Stafford, James Cook

(Postdocs and Students) Gloria S. Forkuo, Margaret L. Guthrie, Nina Y. Yuan, Amanda N. Nieman, Revathi Kodali, Rajwana Jahan, Michael R. Stephen, Michael M. Poe, Guanguan Li, Olivia B.Yu, Benjamin D. Hartzler, Nicholas M. Zahn 

Columbia University: Gene T. Yocum and Charles W. Emala

University of Vienna: Marco Treven and Margot Ernst

Publications:

  1. Molecular Pharmaceutics 2016, 13(6), 2026-2038.
  2. American Journal of Respiratory Cell and Molecular Biology 2016, 64(4), 546-53.
  3. American Journal of Physiology - Lung Cellular and Molecular Physiology 2015, 308(9), L931-42.

 Background:

Asthma is a chronic inflammatory disease of the airways, which in the United States affects over 39.5 million people including 8.7 million children. The disease is characterized by three major features: inflammation, mucous production, and airway hyper-responsiveness. The mainstays of asthma management include anti-inflammatory agents, including inhaled corticosteroids used alone or in combination with potent bronchodilators, such as β2 adrenoceptor agonists. The disease may become resistant to these traditional therapies and the chronic use of these medications is associated with adverse side effects, thus new therapeutics are needed to manage this major public health problem.

GABA(A) receptor Figure 1. Crystal Structure of pentameric GABA(A) receptor (all beta subtypes)

The GABAA family of receptors (GABAAR), which are well-established drug targets for central nervous system disorders, are a promising new pharmacological target to alleviate asthma symptoms. Importantly, GABAAR have been shown to mediate immune-modulatory effects and airway smooth muscle (ASM) relaxation in the lung. GABAAR are heteropentameric ligand-gated chloride channels consisting of combinations of 19 different subunits (α1–6, β1–3, γ1–3, δ, ε, π, θ, ρ1-3). The subunit compositions of the receptors impact ligand selectivity, which has led to the development of subtype-selective drugs with restricted pharmacological effects, kinetics, and regional CNS effects.

Goal: 

Our goal is to develop new systemic therapeutics to alleviate bronchoconstriction based on subtype-selective GABAA receptor modulators.

Approach:

Expression of GABAA receptor subunits was identified in mouse lungs and the effects of α4-subunit-selective GABAAR modulators XHE-III-74EE and its metabolite XHE-III-74A were investigated.

PowerPoint Presentation Figure 2. Screening paradigm

In a murine model of asthma (ovalbumin sensitized and challenged BALB/c mice), we observed that chronic treatment with XHE-III-74EE significantly reduced airway hyper-responsiveness. In addition, acute treatment with XHE-III-74A but not XHE-III-74EE decreased airway eosinophilia. Immune suppressive activity was also shown in activated human T-cells with a reduction in IL-2 expression and intracellular calcium concentrations [Ca2+]i in the presence of GABA or XHE-III-74A, whereas XHE-III-74EE showed only partial reduction of [Ca2+]i and no inhibition of IL-2 secretion. However, both compounds significantly relaxed pre-contracted tracheal rings ex vivo. Overall, we conclude that the systemic delivery of a α4-subunit-selective GABAAR modulator shows good potential for a novel asthma therapy, however, the pharmacokinetic properties of this class of drug candidates have to be improved to enable better beneficial systemic pharmacodynamic effects.