LPS

An innovative combination of methods to identify and study how macrophages function could potentially revolutionize the diagnosis and treatment of various diseases. Macrophages play a critical role in the immune system by fighting infections and aiding in tissue repair. Understanding how these cells are activated in different scenarios is important for developing new medical treatments. However, identifying and studying macrophage activation has been challenging due to the complex nature of these cells and their responses. The research team identified a protein called colony stimulating factor 1 receptor (CSF1R) as a reliable marker for monocytes and dendritic cells in blood and macrophages in tissues -- allowing for the clear identification and separation of different sample types. The new method works reliably for people of all ages and sexes. Dr Fernando Martinez Estrada, who led the research project and is Senior Lecturer in Innate Immunology in the School of Biosciences at the University of Surrey, said: "We have developed a method using CSF1R that can identify all types of Mononuclear phagocyte system cells in the body. This marker is incredibly useful for studying these cells in both health and disease, and it unlocks exciting new possibilities for cell isolation and quantification for diagnosing and monitoring various conditions with a single cell marker." The study developed a set of tools to understand and check how these immune cells respond when they are activated. These tools focus on signals in the body, including IL-4 (involved in healing and fibrosis), steroids (deactivation), IFNγ (fights infections), and LPS (a bacterial product that causes inflammation). The research team also described a novel concept that they call Macrophage Activation Mosaicism. This means that macrophages do not simply switch between the canonical two states previously described; instead, they can exhibit a mix of activation characteristics, reflecting the complexity of real tissue environments. Dr Federica Orsenigo, co-author of the study, explains further: "This discovery is significant because it changes how we perceive macrophage activation. "Recognising that macrophages can have mixed activation status helps us better understand their roles in different diseases and could lead to more targeted and effective treatments." Emeritus Professor Siamon Gordon, co-author of the study from the University of Oxford, said: "Therapies that seek to re-educate macrophages are widely sought. However, the tools to measure activation are underdeveloped. Having a robust multi-gene tool to study macrophage activation can help in drug screening, identify drugs that revert macrophage activation, and eventually help with patient characterisation and personalised medicine."

Paper Published in 'Biomedicines' Highlights MOA, Links Biomarker Changes to Positive Clinical Outcomes PALO ALTO Calif., Dec. 1, 2022 /PRNewswire/ -- Neuvivo today announced the publication of a peer-reviewed paper titled: "Macrophage Targeted Sodium Chlorite (NP001) Slows Progression of ALS through Regulation of Microbial Translocation". The goal of the biomarker-focused study was to test the relationship between NP001 macrophage-targeted immune regulation and the theory that microbial translocation contributed to ALS progression. "The current study links the regulation of the innate immune system by NP001 with ALS disease modification." – McGrath, MD, PhD Published in the journal 'Biomedicines', the peer-reviewed study shows a clear relationship between microbial translocation, inflammation, and disease pathogenesis. Microbial translocation is a process that occurs when bacteria from the gut break through the epithelial barrier and leak into the bloodstream. This initiates a self-perpetuating cycle of inflammation now shown to be directly related to the pathogenesis of ALS and potentially other diseases. NP001 treatment has been shown to restore the normal process of resolution in the inflammatory cycle and in so doing, restore the integrity of the epithelial barrier in the gut – halting damaging microbial translocation. In this study, the immunoregulatory activity of NP001 treatment has been confirmed via the normalization of key blood biomarkers. Mechanism of Action "We have long-postulated that NP001, as a regulator of the innate immune system, restores the balance between macrophages that initiate inflammation and those that promote wound healing," said Michael McGrath, MD, PhD, CSO Neuvivo and Professor Emeritus of Medicine, UCSF. "The current study links the regulation of the innate immune system by NP001 with ALS disease modification, an approach potentially applicable to other inflammatory diseases. ALS was traditionally considered to affect primarily the central nervous system, but recent research supports what we have postulated – that ALS originates as a systemic immunologic reaction to abnormally processed proteins within neurons, ultimately leading to their dysfunction and death." Study Details Earlier in 2022, NP001's activity in two placebo-controlled, 6-month Phase 2 ALS trials was reported. The post hoc analysis defined a large subset of patients between 40-65 years old and with slightly elevated baseline levels of inflammation who were clinically responsive to NP001 treatment. Data showed that NP001 administration was associated with a significantly greater retention of physical function in patients as measured by the ALSFRS-R scale and a significantly greater maintenance of respiratory function. The current study reported in Biomedicines started by defining groups of ALS patients from the Phase 2A NP001 clinical trial that had clear slowing of disease progression compared to controls. Blood biomarkers from the two groups were then measured to determine whether any changes over the 6-month study would be linked to a positive clinical outcome in drug treated patients as compared to controls. Biomarker Data Biomarker data showed that factors associated with harmful microbial translocation (LPS, LBP and HGF), monocyte trafficking (sCD163) and inflammasome activation (IL-18) were significantly decreased in NP001 recipients as compared to placebo over 6 months. Biomarker values that significantly increased were those associated with suppression of inflammation (IL-10, neopterin) and wound healing (EGF). Plasma levels for IL-6, IL-8 and TNF-α were within the normal ranges and relatively stable over the 6-month study. A total of 9 biomarkers showed notable changes in the blood of patients treated with NP001 as compared to controls, linking a slowing of ALS disease progression with the regulation of microbial translocation. Patient Subsets "ALS is now recognized as such a heterogeneous disease that in 2019 the FDA published guidelines encouraging treatment developers to identify subsets of patients most responsive to their therapeutic approach," said Ari Azhir, PhD, CEO, Neuvivo. "This biomarker-based investigation utilized a patient population clinically responsive to NP001 - potentially a large subset - and we saw that macrophage regulation led to slowing, and in some cases halting of disease progression over the 6-month study. NP001 is currently the only treatment in development with a known mechanism of action linking biomarker changes to positive clinical outcomes in a subset of ALS patients. We are working to make treatment available as quickly as possible to people currently living with ALS who may benefit." Biomedicines Publication – Open Access: Biomedicines | Free Full-Text | Macrophage-Targeted Sodium Chlorite (NP001) Slows Progression of Amyotrophic Lateral Sclerosis (ALS) through Regulation of Microbial Translocation (mdpi.com) Editor's Note: The macrophage is the most primordial cell in the innate immune system. It is a type of white blood cell involved in the functioning of the inflammation-resolution cycle. Normally, in response to infection, a subset of macrophages become inflammatory and another subset become wound healing to maintain equilibrium. In ALS, the process is compromised, resulting in unchecked inflammation. Macrophage-targeted treatment restores the normal functioning in the epithelial barrier and throughout the body. About Neuvivo: Neuvivo is a private, late-clinical stage biopharmaceutical company developing advanced treatments for ALS and other neurodegenerative diseases. The company was formed by industry leaders and scientists, focused on improving the prognosis for patients diagnosed with ALS and a range of diseases for which few current treatment options exist. Lead candidate NP001 has been shown to be effective in a large subset of people living with ALS and has an exceptional safety profile. Neuvivo is working to make this treatment broadly available to patients as soon as possible. For more information please visit: Contact: Jennifer Larson 415 409 2729 Jennifer@neuvivo.com