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Enterin and Their Collaborators at NIH Announce That Alpha-Synuclein, the Culprit in Parkinson’s Disease, is Core and Central to Normal Immune Function
Philadelphia, January 11, 2022
Enterin Inc., a privately held, Philadelphia-based, clinical-stage biopharmaceutical company pioneering novel treatments for neurodegenerative and metabolic diseases, announces the publication of a paper entitled “Alpha-synuclein, the culprit in Parkinson’s Disease, is required for normal immune function.”
Alpha-synuclein (αS), the pathologic protein associated with Parkinson’s Disease (PD), appears to be essential for the immune protection of the abdominal cavity. Furthermore, infections in the GI tract can cause accumulation of αS within the entire nervous system, potentially contributing to the development and/or progression of PD, according to scientists at the National Institutes of Health (NIH) and their colleagues, the founders of Enterin, Inc.
αS is causally involved in the development of PD as a consequence of its accumulation within the peripheral and central nervous system. Although the association between αS and PD was discovered almost 25 years ago, its role in normal vertebrate physiology has remained obscure. Recent studies have demonstrated that the presence of a functional αS gene confers survival benefit to mice infected with a neurotropic virus.
The Enterin and NIH teams had previously shown that αS is induced in the enteric nervous system of children who contract a norovirus infection and that it potently attracts components of the immune system such as macrophages and neutrophils and activates dendritic cells to alert the immune system of the specific pathogen encountered.
In this study, published today in the journal Cell Reports, the NIH team shows that αS is critical for the development of a normal immune response to bacterial components introduced into the peritoneal cavity. The authors show that the mice lacking the αS gene cannot recruit immune cells to the site of infection nor induce pathogen-specific immune responses. Remarkably, the animals fail to mount an effective immune response following vaccination. Conversely, when exogenous αS is introduced into the peritoneum, both the innate and adaptive immune response is enhanced. αS appears to enhance the immune response by activating macrophages and inducing the maturation of dendritic cells. Furthermore, they show that nerve cells are the sources of αS, and that infection in the GI tract “alerts” neurons in other locations, inducing widespread production of aS throughout the nervous system, with the highest concentrations produced closest to the site of infection. These findings suggest αS may provide a unique link between the nervous and immune systems. These data also establish that αS plays a critical role in the induction of the normal immune response and help explain the lack of an immune response to infection observed in the αS-/- mice. This study adds to the growing body of evidence that αS accumulates within the nervous system of individuals with PD as a result of an immune response.
”Until this federally-funded study, the importance of αS in mounting an effective immune response was poorly understood,” says the study’s senior author, Joost Oppenheim, M.D., Ph.D., Head, Cellular Immunology Section, National Cancer Institute. “"My laboratory has described the importance of ’alarmins‘ in innate and adaptive immunity. Alarmins are endogenous proteins that both alert and direct the immune system to effectively tackle an infectious insult. αS appears to be an alarmin. The connection between neuronally derived αS and the eventual development of PD remains to be resolved.”
“This study demonstrates beyond the shadow of a doubt that aS made by nerve cells is central to mounting a normal immune response to infection,” says the study’s co-senior investigator, Michael Zasloff, M.D., Ph.D., Scientific Director of MedStar Georgetown Transplant Institute and co-founder and CSO of Enterin, Inc. Enterin’s co-founder and CMO, and co-author, Denise Barbut M.D., FRCP., adds that “What’s remarkable is the rapid induction of aS in nerves at great distances from the site of the infectious stimulus. It is conceivable that aS production within the brain in Parkinson’s disease is triggered indirectly by a neural signal emanating from the site of a remote infection rather than being physically transported from the periphery.”
The study was funded by the National Institute of Health.
About Enterin Inc.
Enterin Inc. is the first company to develop novel compounds that repair the dysfunctional gut-brain axis in patients with neurodegenerative diseases. Enterin Inc. is pioneering the medical community’s understanding of the link between infections, dysfunction of the enteric nervous system (ENS) and the onset and progression of neurodegenerative disease. Enterin’s lead compound, ENT-01, displaces membrane-bound alpha-synuclein (αS) aggregates from nerve cells in the ENS and improves neural signalling between the gut and the brain. Enterin Inc. is now progressing ENT-01 through Phase 2 clinical trials in an attempt to reverse the neurologic symptoms of Parkinson’s disease. The second compound, ENT-03, increases insulin sensitivity by acting at the level of the brain and acutely normalizes blood sugar in diabetic mice. ENT-03 is being developed for the treatment of diabetes, obesity and Alzheimer’s disease. Studies in humans will begin in 2022.
