An unmet need in the treatment of allergic asthma is an effective therapeutic strategy that focuses on an underlying cause of the disease rather than merely treating or managing its symptoms. At least one well- accepted underlying contributor to the pathophysiologic expression of asthma is an over-expressed and dysregulated T helper type 2 (Th2)-mediated immune response to various environmental antigens. Recent studies have shown that the pro-inflammatory, complement-derived component C5a plays an important role in regulating this Th2-dominated response in the airway in order to maintain a proper Th1/Th2 immune balance. These studies showed that C5a engages C5a receptor (C5aR)-bearing airway dendritic cells (DC) in such a way as to downregulate this Th2 response and, apparently, allow for the expression and maintenance of a beneficial Th1/Th2 balance. Thus, a potential treatment approach for asthma would be the use of a C5a mimetic capable of upregulating Th1 cytokines via selective engagement of C5aR-bearing airway DCs as a way to re-establish and maintain this beneficial Th1/Th2 balance, but without engagement of C5aR-bearing airway-infiltrating inflammatory cells. Toward this end, a response-selective agonist of C5a known as EP67 has been developed. EP67 activates C5aR-bearing DCs to release Th1 cytokines yet lacks any ability to activate C5aR-bearing inflammatory neutrophils. The long-term goal of this project is to move EP67 along a commercialization pathway toward its use as a safe and effective method for treating asthma in humans. The main objective of this Phase I study, which is a crucial step in pursuit of this goal, is to demonstrate the potential protective effects of EP67 in vivo in well-established and human-relevant murine models of asthma. This objective will be approached by the following specific aims: 1) To demonstrate therapeutic efficacy of EP67 in preventing the induction of the Th2-biased airway inflammation and AHR utilizing acute allergen challenge models in mice;and 2) to demonstrate therapeutic efficacy of EP67 in reversing established airway inflammation and AHR utilizing chronic allergen exposure models in mice. This use of EP67 is significant, because it mediates the establishment of an immunologically beneficial Th1/Th2 environment and, consequently, could have a positive impact on the treatment of asthma by providing a safe and effective method of addressing an underlying cause of the disease by selectively enhancing the beneficial effects of C5a rather than indiscriminately blocking its deleterious effects. Other features of EP67 that support its innovative use as a commercial candidate for the treatment of asthma include: 1) the economy and ease of its production in large and highly purified quantities;2) its long-term (years) stability at room temperature;3) its high solubility in water;4) its ease of administration intranasally;and 5) its lack of toxicity.
The proposed research is relevant to public health because it will make available a convenient, effective, and unique way of treating allergic asthma - a disease that is on the rise worldwide. This disease target and treatment approach is relevant to the mission of the NIH that pertains to understanding the immunologic mechanisms responsible for allergic disorders and the development of therapeutics that could help treat these disorders.
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