Emmanuel Mignot

Emmanuel Mignot, MD, PhD

Emmanuel Mignot, MD, PhD

Craig Reynolds Professor of Sleep Medicine, Stanford University

Dr. Mignot is the Craig Reynolds Professor of Sleep Medicine at Stanford University. A leader in sleep research and medicine, he discovered that the pathophysiological basis of human narcolepsy is the loss of ~20,000 hypothalamic orexin/hypocretin neurons, leading to deficient neurotransmission. In the process, he was the first to positionally clone a disease gene in the dog (HCRTR2 mutations causing canine narcolepsy), identifying orexin/hypocretin as a key sleep regulator. He also identified HLA-DQ0602, T-cell receptor genes, and other immune polymorphisms as major human narcolepsy susceptibility genes across ethnic groups, showing that they act together to promote a highly selective autoimmune process. He found that narcolepsy is triggered by specific flu strains and that molecular mimicry between influenza and orexin sequences in the context of DQ0602, trigger the autoimmune process, explaining these associations. He also previously characterized pharmacologic mechanisms of major narcolepsy medications and established measurement of cerebrospinal fluid hypocretin-1 as a new diagnostic tool for narcolepsy, a test used worldwide. This work is now also leading to novel pharmaceutical agents, hypocretin/orexin antagonists, as insomnia therapies and orexin agonists for narcolepsy. These latter drugs, currently in clinical trials, have been shown to reverse human narcolepsy symptoms in pilot phase I studies at low doses. His expertise extends beyond narcolepsy; for example, he studies the pathophysiology of autoimmune encephalitis and the role of adaptive immune responses in neurodegenerative diseases. He also developed highly performant machine learning software for high throughput scoring of polysomnographic sleep studies. These are now used for large scale genetic studies of objective sleep trait and sleep disorders.