September 2022 issue, BioElectRx Business Report
September 30, 2022 | Neural regulation of immunity is not a new idea. Way back in 2000, Kevin Tracey and colleagues published their findings about the effects of efferent vagus nerve signaling and its role in modulating inflammation. The investigators showed that lethal endotoxaemia in rats could be inhibited by direct electrical stimulation of the vagus. The researchers saw inhibited TNF synthesis in the liver, attenuated peak serum TNF amounts, and prevention in the development of shock. And a star target was born.
In the years since that 2000 publication, there have been more than 26,000 papers, reviews, chapters, and other presentations looking at vagus nerve stimulation and more than 70% of those papers focused on VNS and inflammation. The vagus nerve became a darling of research and commercial opportunities alike.
SetPoint Medical, founded six years after the seminal paper, has since raised almost $200 million in pursuit of commercial applications for VNS to control rheumatoid arthritis and Crohn’s disease. Significant improvements to patients with RA have been demonstrated and their Phase 2 study, “Reset RA” was recently approved. This tells us, at the very least, that the therapy is not failing. Their patients will tell you that it has been life changing.
Over the past two decades, Tracey and the Feinstein Institutes for Medical Research have continued to develop and grow our understanding of the role of the neural control of immunity. In fact, they have developed a center within the Institution, the Institute for Bioelectronic Medicine, as well as an open access, peer reviewed journal Bioelectronic Medicine, and a recurring meeting, the Bioelectronic Medicine Summit, happening again this fall in New York. The Summit includes a broad range of breakthroughs in a wide range of research and a session chaired by Eric Chang on the neuroregulation of immunity. The panel will feature research updates from Gloria Choi of MIT, Asya Rolls from Technion, Brian Kim of Mount Sinai, and Jeremy Borniger from Cold Spring Harbor Laboratory.
The research community has, in most cases, elevated the vagus nerve to savior status but others remain unconvinced. VNS is an approved treatment for epilepsy and depression and as a rehabilitation aid in stroke, although in these therapies the immune response is not targeted. Advanced progress has been made in Crohn’s disease, rheumatoid arthritis while new interest in multiple sclerosis, long COVID and significant investments have also been made in the investigation of the vagus nerve and its role in controlling the immune response for disease states including uncontrolled bleeding and a wide range of other inflammatory diseases. But! The vagus nerve might not be alone in the fight against the inflammatory response.
Kenneth Chapman of Spine and Pain Institute of New York is looking to the dorsal root ganglion as a new target to control osteoarthritis in a 30-patient clinical trial, sponsored by Abbott. The study will be looking at biomarkers to determine if there are any changes in cartilage degradation or even immune biomarkers as possible metrics of disease modification.
Wenfei Han and Ivan de Araujo of Icahn School of Medicine at Mount Sinai also looked at DRG afferent signaling as an alternative for vagal afferent signaling from internal organs. Their study in genetically-modified mice demonstrated that sympathetic afferents in DRGs play a critical role in relaying sensory information from the stomach and intestines to vagal centers in the brainstem, while signaling from traditional vagal afferents in the nodose ganglia was not important.
Also, Colin Reardon at UC Davis observed in mice that sympathetic afferents in DRGs play a neuroprotective role during bacterial intestinal inflammation.
If DRG proves to successfully regulate the immune response, perhaps we are no longer wed to the vagus and our procession to the all-night chapel of Elvis. The field has spent a great deal of time and effort examining on-target effects. How much do we really know about off target effects when we haven’t yet been measuring anything outside of what we’re looking for? Foregone conclusions may not be so foregone anymore.
