Complexa researches and develops highly selective endogenous and nitro and keto fatty-acid (NFAs and KFAs) cell signaling agents that mediate the body’s main inflammatory and fibrosis pathways. These include the up-regulation (‘enhancing’) of cytoprotective and anti-inflammatory and pathways such as Nuclear Factor (erythroid-derived 2)-like 2(Nrf2), Hemeoxygenase-1(HO-1), and Heat Shock Factor (HSF) and down-regulation or blockade of pro-inflammatory pathways such as Nuclear Factor Kappa B (NF-ĸB). When exposed to chronic disease stress and inflammation, levels of endogenous NFAs are depleted within the body and become inadequate to impact disease progression. Complexa’s technology replenishes the supply of NFA to restore disease appropriate levels of Nrf2 activation and Nf-kB inhibition thus promoting the repair of tissue injury and reversal of fibrosis and inflammation. Complexa has generated extensive pre-clinical model and clinical disease data across various forms of fibrosis and inflammation related conditions from researchers world-wide in over 100 high impact citations. Complexa plans to enter Phase 2 clinical trials in two orphan diseases with its lead compound CXA-10 in 2017.
Nitro Fatty Acids (NFAs)
Crucial cell signaling actions result from the enzymatic and chemical oxidation of unsaturated fatty acids to derivatives that modulate neurotransmission, vascular function and inflammatory responses. Nitro-Fatty Acids (NFAs) represent a novel class of anti-fibrotic, metabolic, and anti-inflammatory signaling mediators.
Importantly, NFAs are highly selective and reversibly react with susceptible transcription factor and key receptor thiols to modulate gene expression via post-translational modification of susceptible protein residues. Fatty acids are dynamic signaling mediators that link the biochemical status of cells with gene expression.
Two critical discoveries created the foundation of knowledge that led to the identification of NFAs as endogenous signaling mediators. First, the discovery that oxygenation of unsaturated fatty acids forms autocrine and paracrine signaling mediators (prostaglandins and leukotrienes) was awarded a Nobel Prize in 1988. Subsequently, nitric oxide (NO) was described as a mediator of vascular relaxation and modulator of inflammation, resulting in a 1998 Nobel Prize. Complexa’s founders have been guided by these insights and have discovered that NO influences the signaling actions of unsaturated fatty acids and generates a new class of signaling mediators as by products.
Mechanism of Action
The mechanism of action of CXA-10 is to adduct key signaling proteins that are involved in inflammatory processes, thereby modulating their activity to lead to cellular and tissue-protective anti-oxidant, anti-inflammatory and anti-fibrotic effects.
Key Signaling Pathways
NF-κB (nuclear factor kappa B)
NF-κB is the body’s main inflammatory pathway and controls transcription of DNA in almost all animal cell types. It is involved in cellular responses to pro-inflammatory stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. It controls many genes involved in inflammation, and is chronically active in many inflammatory diseases, such as inflammatory forms of kidney disease, pulmonary arterial hypertension, Sickle Cell Disease, and others. NF-κB has been linked to cancer, autoimmune diseases, neurodegeneration, and has been implicated in processes of synaptic plasticity and memory. Reversible blockade via direct binding to NF- κB is one the key attributes of Complexa’s technology.
The Nrf2 pathway is one of the body’s primary cellular defense mechanisms against the cytotoxic effects of oxidative stress and increases expression of multiple proteins and enzymes involved in oxidative defense and anti-inflammatory pathways. It is a highly-conserved evolutionary pathway, originating in unicellular organisms. Under oxidative stress, Nrf2 travels to the nucleus and binds to a DNA promoter and initiates transcription of anti-oxidative genes and their proteins. Nrf2 is ubiquitously expressed with the highest concentrations (in descending order) in the kidney, muscle, lung, heart, liver, and brain. Under a variety of disease conditions, however, Nrf2 activity may be suppressed to levels too low to be effective in combating the disease related inflammation and other negative effects.