α7nAChR Program

Led by Professor Lawrence Steinman and Dr. Jonathan Rothbard, stanford

Biotech Company Graphic

Smoking cessation induced Ulcerative Colitis (UC)

Excessive inflammation and TNFα synthesis cause morbidity and mortality in a spectrum of human diseases including sepsis, rheumatoid arthritis, and inflammatory bowel disease. TNFα specific antibodies that inhibit signaling, and represent the single most profitable segment of human therapeutics, are administered by intravenous injection. Identification of a small molecule surrogate for the biologic therapeutics has been prohibitively difficult due to the unusual structural features of the binding of TNF by its receptors. The mechanism has evolved to allow only trimers of TNFα to be agonists of the receptors, which form only in the case of sufficiently high local concentrations. Monomers of TNFα are inactive ligands. A further complication is the receptors are also trimeric aggregates. Consequently, inhibiting such a complex interaction with a small, orally bioavailable structure has not been accomplished. An alternative strategy is to inhibit signaling pathways that induce TNFα. A highly conserved, endogenous neurological pathway mediated by the vagus nerve detects and limits inflammation discovered by our collaborator, Dr. Kevin Tracey.

What is Inflammatory Reflex

The Inflammatory Reflex is defined as the afferent arm of the vagus nerve detecting inflammatory cytokines and relaying their location to the brain, which in turn activates the efferent arm to transmit signals to release immunosuppressive acetylcholine specifically to the site. Alpha 7 nicotinic acetylcholine receptor (a7nAChR) agonists are known to reduce inflammation, but are thought to act by binding the receptor on macrophages, lymphocytes, and other immune cells. The experiments in this proposal are designed to establish an alternative mechanism; diffusion across the blood brain barrier, directly binding α7nAChR in the brain, and stimulating the Inflammatory Reflex.

Possible Revolutionary Treatment of Inflammation

A potent, selective, orally available, small molecule capable of activating the vagus nerve and the Inflammatory Reflex to provide an anti-inflammatory signal to inflamed regions of the body would revolutionize treatment of inflammation. Work by our collaborators, led by Dr. Kevin Tracey and Dr. Sangeeta Chavan, have established the vagus nerve actively both detects and treats inflammation locally. Consequently an α7nAChR agonist could be administered systemically, but therapeutically be effective locally. The clinical target will be ulcerative colitis that develops in patients who recently have stopped smoking.

Competitive Advantages

Existing Therapies are Sub-Optimal

Orally Bioavailable Anti-TNF Advantages