PROGENRA INC — Department of Health and Human Services SBIR Phase I: NIAID

Description

Asthma is a major public health problem affecting million people worldwide While no cure is available symptoms can be managed with corticosteroids and agonists which can exert deleterious side effects Improved targeted therapies are needed for steroid resistant and other forms of asthma A complex disease asthma entails chronic inflammation hyper reactivity and remodeling of the airways and immunity driven by TH and TH cells contributes to the pathogenesis of asthma subtypes Cytokines secreted by these immune cells act to recruit eosinophils and neutrophils leading to the pathology of asthma further crosstalk between TH and TH responses ultimately leads to further amplification and elevation of inflammation Targeted suppression of TH and TH differentiation and or responses is the general approach taken here for treating the underlying drivers of asthma In particular the ubiquitin pathway regulates immune responses and ubiquitin based drugs may have utility in controlling asthma For example the E ligase Itch suppresses both TH and TH differentiation and cytokine production upon activation by Nedd family interacting protein Ndfip Progenra has identified small molecule Ndfip mimetics which are able to activate Itch impairing IL production and promoting Treg rather than TH cell differentiation Recently USP a deubiquitylase has been shown to be critical for TH differentiation by stabilizing TH specific transcription factor RORgammaT and pharmacological inhibition of USP blocks TH differentiation Thus one can selectively target TH and TH differentiation by modulating USP function It is therefore proposed here to discover and develop selective small molecule inhibitors of USP these are expected to limit TH differentiation dampening inflammatory asthmatic responses In addition USP inhibitors will be combined with Progenraandapos s small molecule Ndfip mimetics Itch activators to selectively impair TH and TH differentiation To accomplish this therapeutic goal high throughput screening for USP inhibitors will be conducted employing Progenraandapos s screening platform and member small molecule library Cellular proof of concept assays will be conducted on selected hits to evaluate their effect on TH differentiation and cytokine production in relevant in vitro models In Phase II lead optimization and additional preclinical studies will be performed with selected inhibitors to ascertain their ability to modulate USP functions and to dampen inflammation in relevant mouse models The ultimate commercial goal is the development of novel small molecule agents that can be used in combination to treat steroid resistant asthma Asthma is a complex disease driven by T cells of the immune system that activate inflammatory cytokine secretion causing asthma symptoms Progenra has discovered small molecule ubiquitin pathway modulators that can reduce cytokine production by interfering with the T cells A second ubiquitin pathway enzyme USP has been found to activate T cell dependent cytokine production In this project inhibitors of USP will be developed to use alone or in combination with the original T cell modulators to eradicate the symptoms of asthma produced by inflammatory cytokines the combination treatment is expected to be very powerful