Asthma is a chronic disease with considerable morbidity and no cures. Symptomatic treatment is efficacious but produces significant adverse effects. Thus, improved, targeted therapies for asthma are needed. Asthma develops when T cells (CD4+) differentiate to effector T cells, which secrete cytokines that assist in the recruitment and proliferation of various innate immune cells into tissues. Th2 and Th17 cells contribute to pathogenesis by secreting inflammatory cytokines that induce the influx of neutrophils and eosinophils, leading to airway inflammation. Targeted suppression of pro-inflammatory cytokines and chemokines are thus attractive approaches to attenuate allergic responses in asthma. It is proposed here to achieve this therapeutic aim by exploiting the ubiquitin proteasome pathway. Protein ubiquitylation is a key regulatory mechanism of innate and adaptive immune systems;ligases such as Itch, Nedd4 (HECT), Cbl-b, and MID1 (RING) regulate immune responses in asthma. Nedd4 ligases including Itch negatively regulate allergic immune responses. Notably, genetic disruption of Itch in mice or humans causes multi-system immune disorders and lung inflammation. Several Nedd4 family E3 ligases exist in an auto-inhibited state;Itch is kept inactive by the N-terminal auto-inhibitory C2 domain and is activated by adapter proteins such as the Nedd4- family interacting protein 1 (Ndfip1), which relieves the auto-inhibition. Ndfip1 promotes activity of multiple E3 ligases, thereby limiting both Th2 differentiation and IL-4/IL-5 /IL-13 production in T cells as well as the pathogenicity of Th17 cells, and Ndfip1-/- mice develop inflammation in the lungs characteristic of that induced by Th2 cytokine producing T cells. Moreover, SNPs in Ndfip1 are found associated with asthma and atopic dermatitis. Thus, Ndfip1 is a key negative modulator of T cell regulation and allergic inflammatory responses, and therapeutic mimetics of Ndfip1 should selectively activate ubiquitylation cascades to limit Th2 and Th17 cytokine production and thereby diminish allergic inflammation. Such mimetics will be identified in high throughput screening of small molecule libraries with the use of Progenra's E3 ligase assay technology adapted to identify activators of Itch. Cell proof of concept assays will measure the impact of selected small molecule agonists in Type 2 helper T cells and relevant allergy response models. In Phase II, lead optimization and additional preclinical studies will be performed with the best agonists to ascertain their ability o modulate Itch functions as well as to attenuate inflammation in relevant mouse models.
Improved, targeted therapies are needed to treat asthma, a serious chronic disease for which only symptomatic therapies are now available. A potential therapeutic target has been identified in the ubiquitin pathway - an enzyme called Itch, which acts to reduce the production of inflammatory cytokines, which are principal causes of asthma. It is proposed to find small molecules that will activate Itch and thereby serve as preventive therapy.
