Bioelectronic Medicine The New Frontier Of Inflammatory Disease Treatment

Bioelectronic Medicine The New Frontier Of Inflammatory Disease Treatment

The rapid pace of technological evolution over the past several decades has dramatically changed the way we live and work, and it is also changing the way medicine is practiced. The convergence of technology, molecular medicine and molecular biology will enable development of devices and technologies to catalyze advances in mechanistic understanding of disease. Individuals positioned to lead this effort are at the spearpoint of where molecular biology meets technology and will be creating a revolutionary new future: bioelectronic medicine.

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The Manhasset, New York based Feinstein Institute for Medical Research — the research arm of the North Shore-LIJ Health System, in cooperation with SetPoint Medical Inc., a Valencia, California-based biomedical technology company, have released research results on the therapeutic potential of vagus nerve stimulation. In a paper published in the journal Bioelectronic Medicine, the Feinstein Institute for Medical Research’s president and CEO Kevin J. Tracey, MD, and his colleagues at the Institute, explore how low-level electrical stimulation interacts with the body’s nerves to reduce inflammation, a fundamental goal of bioelectronic medicine.

Prior to this study, it was not understood which vagus nerve fiber types were responsible for reducing the body’s inflammatory activity. The Bioelectronic Medicine paper’s findings indicate that activation of either motor or sensory vagus nerve bundles can diminish inflammation and help address diseases such as Inflammatory Bowel Disease.

KevinTraceySetPoint Medical’s scientific platform is based on the Inflammatory Reflex — the natural mechanism by which the central nervous system regulates the immune system. SetPoint co-founder and now Feinstein Institute for Medical Research president and CEO Kevin Tracey discovered the Inflammatory Reflex pathway, publishing his findings in the journal Nature in May 2000. Since then, the Inflammatory Reflex has been characterized in more than 100 peer reviewed papers in leading scientific journals. Anti-inflammatory potency comparable to leading drugs has been demonstrated in multiple animal models. The company is currently conducting human trials in rheumatoid arthritis at four European centers.

SetPoint’s approach uses vagus nerve stimulation to activate the Inflammatory Reflex. Published literature suggests the Inflammatory Reflex produces a potent systemic anti-inflammatory effect. The company’s novel platform consists of an implantable miniature neuromodulation device, wireless charger and iPad control application.

On December 4, 2014 SetPoint Medical announced the start of clinical testing to assess safety and efficacy in Crohn’s Disease, in Orlando, Florida for “Advances in Inflammatory Bowel Diseases,” the Crohn’s & Colitis Foundation’s annual clinical and research conference.

SetPoint has also completed a first-in-human open-label proof-of-concept trial in rheumatoid arthritis. The study helps validate neuromodulation as a breakthrough approach to treating autoimmune inflammatory diseases. SetPoint’s approach is designed to supplement the body’s natural Inflammatory Reflex by providing ‘built-in’ therapy at a lower cost and is intended to improve safety compared with drugs or biologic solutions.

The major focus of Dr. Tracey’s laboratory is inflammation, the physiological and immunological response to infection and injury, and the mechanism by which neurons control the immune system.

“Identifying the exact role of the different nerve bundles in the inflammatory reflex bolsters our understanding of the relationship between the central nervous system and the vagus nerve,” says Dr. Tracey. “Furthermore, we now know that stimulating the vagus nerve for as little as half a millisecond is enough to inhibit tumor necrosis factor (TNF) production.”

Focused on defining the body’s mechanisms that normally present the overproduction of TNF, Dr Tracey’s research led to discovery of the inflammatory reflex, initially by electrically stimulating the vagus nerve to control macrophage TNF production via alpha-7 nicotinic receptors. These findings spanned immunology and neuroscience, and have engendered widespread interest in the fundamental role of neural reflexes in maintaining immunological homeostasis.

Dr. Tracey also discovered the direct inflammatory action of HMGB1, first reporting this in the journal Science, which initiated a new field that has grown explosively. The identification of a critical cysteine of HMGB1 that interacts with TLR4 to stimulate cytokine release and inflammation reveals the critical role played by HMGB1 at the intersection of sterile and infectious inflammation.

In the early 1980s, Dr Tracey participated in the discovery of the direct inflammatory activity of tumor necrosis factor-alpha (TNF), and first reported that specific anti-TNF monoclonal antibodies can be effectively used as a therapeutic agent. A subsequently expanding field of research confirmed that TNF is a mediator of septic shock (similar to the effects of directly administering TNF to mammals), but not sepsis. This prompted the Tracey lab to search for another mediator of sepsis, culminating in 1999 with the identification of HMGB1, a protein previously known as a DNA-binding transcription factor, as a mediator and drug target in sepsis. The lab continues to focus on this activities and mechanisms of this molecule, and recently revealed the critical role played by the redox structure of the three cysteine residues which directly influence the biological activities of HMGB1 as a proinflammatory cytokine, and chemotactic factor.

Most recently, Dr. Tracey has made discoveries in bioelectronic medicine. Bioelectronic medicine tells nerves to produce the natural chemicals the body uses to cure itself. More specifically, scientists have found that stimulating the vagus nerve inhibits potentially damaging cytokine responses, and protects against organ damage caused by unregulated or excessive cytokine release. In 2011, the Tracey lab reported discovery of a memory T cell subset that secretes acetylcholine in the spleen when activated by signals arising in the vagus nerve. These T cells are regulated by incoming neurotransmissions arising in the brain stem, and respond by producing the terminal neurotransmitter required to complete the inflammatory reflex.

The neural circuit the lab team discovered can be exploited to therapeutic advantage, because application of electrodes to stimulate the vagus nerve (vagus nerve stimulation) protects against damaging inflammation in arthritis, colitis, ischemia, myocardial infarction, congestive heart failure, and other conditions. In November 2012, the lab participated in reporting the first successful clinical trial demonstrating that vagus nerve stimulation can be effective in methotrexate-resistant rheumatoid arthritis patients, as presented at the American College of Rheumatology’s annual meeting.

The importance of the inflammatory reflex in controlling inflammation establishes that the immune system does not function autonomously. Thus, immune responses and adaptation to infection and injury are integrated into host physiology, and coordinated by physiological units of reflex action.

After establishing the neural bundles activated in vagus nerve stimulation, the researchers found that only low-intensity, short-duration, electric pulses were needed to reduce the production of inflammation-inducing cytokines. Repetition of the pulses did not increase the success of the treatment in this experiment indicating that a single stimulating pulse is potentially sufficient.

“Seeing successful results with low-level electrical current is a significant finding,” says Yaakov Levine, PhD, senior research scientist at SetPoint Medical and lead author of a study published in Bioelectronic Medicine last December entitled Neurostimulation Of The Cholinergic Antiinflammatory Pathway In Rheumatoid Arthritis And Inflammatory Bowel Disease (10.15424/bioelectronmed.2014.00008), coauthored by Frieda Koopman, Michael Faltys, Ralph Zitnik, and Paul-Peter Tak.

The same team, plus researchers April Caravaca, Alison Bendele, and, Margriet J. Vervoordeldonk, also coauthored an Open Access research article published in the journal PLOS one in August 2014, entitled Neurostimulation of the Cholinergic Anti-Inflammatory Pathway Ameliorates Disease in Rat Collagen-Induced Arthritis” (DOI: 10.1371/journal.pone.0104530), which found the severity of collagen-induced arthritis is reduced by neurostimulation of the cholinergic anti-inflammatory pathway delivered using an implanted electrical vagus nerve stimulation cuff electrode, and supports the rationale for testing this approach in human inflammatory disorders.

The researchers note that despite significant therapeutic advances, diseases like Inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) still cause significant morbidity and mortality, and the unmet medical need for patients with these disorders remains high.

The study coauthors observe that an important neural-immune regulatory mechanism termed the “inflammatory reflex,” and its efferent arm, the “cholinergic antiinflammatory pathway” regulate innate and adaptive immunity, and that an emerging body of evidence indicates that stimulation of this pathway with implantable medical devices is a feasible therapeutic approach in disorders of dysregulated inflammation.

They go on to describe the underlying biology and preclinical experiments done in standard animal models that provided the rationale for testing in clinical trials, observing that the preclinical development approach comprised elements of classic drug and medical device development, yet had unique features and challenges. They maintain that “bioelectronic medicines” having ideal characteristics of both drugs and medical devices hold great conceptual promise for treatment of systemic diseases in the future. However studies being done today will help determine whether neurostimulation of the cholinergic antiinflammatory pathway (NCAP) has the potential in the nearer term to fulfill the needs of patients, caregivers and payers for an additional potential treatment option for inflammatory disorders, and might thus become one of the first feasible examples of a bioelectronic medicine. This indicates potential for limited side effects, as well as promise for device miniaturization, both of which will be important to bringing vagus nerve stimulation into the mainstream.

SetPoint’s microregulator is designed to supplement the body’s natural Inflammatory Reflex by providing ‘built-in’ therapy at a lower cost and is intended to improve safety compared with drugs or biologic solutions.

SetPoint Medical was named by FierceMedicalDevices as one of 2013’s Fierce 15 device and diagnostic companies, designating it as one of the most promising private companies in the med tech space. The Feinstein Institute, part of the North Shore-LIJ Health System, ranks in the top 6th percentile of all National Institutes of Health grants awarded to research centers. For more information, visit: http://www.FeinsteinInstitute.org

Sources:
The Feinstein Institute for Medical Research
SetPoint Medical

Bioelectronic Medicine

PLOS one

Image Credits:
The Feinstein Institute for Medical Research

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