Novel Bronchodilator Therapy for Asthma, Chronic Obstructive Pulmonary Disease and Cystic Fibrosis by Gα12 Inhibitors and Rho Inhibitors

Figure 1 G α12 signaling and RhoA-dependent activation of the PI3K/ROCK axis Figure 2 G α12 siRNA attenuates carbachol-induced MLC (myosin light chain) phosphorylation in vivo . Reduced MLC phosphorylation indicates human airway smooth muscle relaxation. Carbachol activates G α12 -coupled M3 muscarinic receptors in human airway smooth muscle. Invention Summary: Airway Hyperresponsiveness (AHR), a hallmark of asthma, represents exaggerated airway narrowing in response to contractile agonists such as acetylcholine. Human airway smooth muscle cells (HASMCs) mediate AHR by shortening in response to contractile agonists. Inhibition of calcium sensitization pathways in human airway smooth muscle has been shown to be an effective method of inducing bronchodilation. Due to off target effects in vascular smooth muscle, however, clinical trials of bronchodilators targeting calcium sensitization pathways have been precluded. Accordingly, there is a strong need for alternative approaches to the clinical management of airway obstruction in asthma, chronic obstructive pulmonary disease (COPD), and other inflammatory lung diseases. About 50% of asthma patients currently have uncontrolled symptom. This research approach may overcome the limitations of existing therapy. Rutgers scientists identified a novel target - G α12 signaling - for relaxing human airway smooth muscle. This discovery demonstrates that G α12 plays a crucial role in human airway smooth muscle contraction via RhoA-dependent activation of the PI3K/ROCK axis (Figure 1). In human asthma models, inhibition of G α12 signaling serves as an effective and novel method of inducing bronchodilation, a clinically desirable outcome in asthma treatment (Figure 2). Targeting G α12 signaling may elucidate novel therapeutic targets in asthma. In addition, inhibition of RhoA activation induces bronchodilation in human precision-cut lung slices. Taken together, these findings provide alternative approaches to the clinical management of airway obstruction in asthma, COPD, and any other inflammatory lung disease. Market Applications: Agents and method for therapeutic treatment of asthma, chronic obstructive pulmonary disease, cystic fibrosis and other inflammatory lung diseases. A method for identifying an agent which inhibits contraction or promotes relaxation of an airway smooth muscle cell. Advantages: Novel bronchodilators New modality of treatment Tissue-specific target Intellectual Property & Development Status: Patent pending. Available for licensing and/or collaboration.