Research Project
9679333
ABSTRACT Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed drugs to treat post- traumatic inflammation and pain, although they carry significant risk of serious, dose-dependent adverse events. Corticosteroids, which are an alternative class of anti-inflammatory drugs, are rarely prescribed for post-traumatic inflammation, due to adverse effects on wound healing and their lack of specificity. Thus, there is a great need for novel anti-inflammatory therapies with better safety profiles. There is also a great medical need for novel, safe anti-inflammatory compounds that also have analgesic properties. NaV1.7 is an ion channel that is expressed on primary nociceptors, where they mediate pain. Evidence suggests that NaV1.7 is also expressed on dendritic cells of the immune system, where their function is yet unknown. Chromocell created a novel class of analgesic compounds, CC7442 and structural analogs, that selectively block NaV1.7 and are currently FDA fast tracked in clinical trials to treat pain. As we show within, in a surgical incision model of pain and inflammation, rats treated with CC7442 had markedly reduced paw edema and accelerated resolution of the edema. Another analog, CC8464, is currently completing Phase I human safety trials. In the rat surgical incision model, CC8464 was administered to animals for 7 days and fully resolved edema in 17 days compared to 28 days with Ibuprofen. CC8464 also reduced inflammatory cell infiltration of the pancreas and reduced systemic levels of the pro-inflammatory cytokine, TNFa. Within this project, we will characterize the anti-inflammatory effects of CC7442 in the rat surgical incision model, as well as in vitro using PBMCs. If our hypothesis is correct, then CC7442 will be a first in class analgesic drug to treat post-surgical inflammation and pain by selectively targeting the peripheral, inactivated NaV1.7 channel. Specific Aim 1: Determine local anti-inflammatory effects of CC7442 in the rat surgical incision model. The goal of this aim is to provide molecular or cellular evidence to explain the observed reduction in edema with our NaV1.7 inhibitors and suggest possible mechanisms of action. We will assess inflammatory parameters within the paw, including (a) local levels of inflammatory mediators, (b) infiltration of immune cell subsets, (c) histological assessment of tissue structure and the formation of granulation beds, and (d) changes in NaV1.7 expression. Specific Aim 2: Determine systemic anti-inflammatory effects of CC7442 in surgical incision rat model. In this aim, we will determine effects on inflammatory parameters in blood, including (a) circulating levels of inflammatory mediators and (b) proportions of circulating immune cell subsets. Specific Aim 3: Study effect of CC7442 on human PBMC cytokine secretion in vitro. We will study the effect of CC7442 on inflammatory markers excreted by cultured human PBMCs with and without LPS stimulation. Cytokines secreted into the media will be measured by multiplexed immunoassays. Milestones: Observation of a statistically significant decrease in proinflammatory cytokines and an increase in anti-inflammatory cytokines in the paw and to a lesser extent systemically.
