Strategies for Targeting Neuroinflammation in Treatment

Programming tissue-sensing T cells that deliver therapies to the brain We created a set of brain-sensing T cells programmed to locally deliver therapeutic payloads customized for cancer or neuroinflammation. First, we identified a set of CNS-specific extracellular ligands using publicly available expression data to establish potential brain “GPS” markers. We identified proteins such as brevican (BCAN), which are components of the brain’s highly unique extracellular matrix and might be exploited for tissue-specific recognition. We screened for antibodies against these CNS-specific antigens and used them to build CNS-activated synthetic Notch (synNotch) receptors, engineered receptors that sense an extracellular antigen and respond by inducing a transcriptional response. To demonstrate the therapeutic potential of this approach, we used this platform to locally induce a set of genetically encoded payloads directed toward different CNS diseases. Brain-sensing T cells that induced CAR expression were able to treat primary and secondary brain cancers, including mouse models of glioblastoma and breast cancer metastases, without off-target attack of tissues outside of the brain. Conversely, CNS-induced expression of the immunosuppressive cytokine interleukin-10 (IL-10) ameliorated neuroinflammation in experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. This tissue-targeted cell induction strategy provides two levels of specificity. First, the cell shows anatomically restricted specificity, as cells are only induced in the CNS, and second, the payload (e.g., CAR, cytokine, antibody) has its own intrinsic molecular targeting specificity. This nested, multiscale targeting strategy mimics the principles of natural biological specificity, avoiding potential unwanted systemic cross-reactions of the molecular payload while focusing its actions more effectively on the target tissue. These results suggest that brain-sensing cells could be used as a general platform to treat a broader set of CNS diseases, including brain tumors, brain metastases, neuroinflammation, and neurodegeneration. Although we focused here on targeting the CNS, this concept could be applied to a broader set of tissues. Tissue-targeted therapeutic cells provide an approach to integrating endogenous and disease signals to generate therapies that are more specific and effective. https://lnkd.in/eY5iwWtw

Unlocking the Brain's Inflammatory Code: A Provocative New Angle for Neurodegenerative Diseases Yesterday's study in Nature Medicine (https://lnkd.in/e7X4zBAx) has sparked my interest! It identifies a conserved APOE ε4-associated pro-inflammatory immune signature that persists across the brain and is implicated in multiple neurodegenerative conditions. This isn't just about Alzheimer's; it points to a potentially broader, shared mechanism driven by APOE4. If APOE4 is indeed a key driver of this widespread neuroinflammation, it opens up some fascinating therapeutic possibilities: Targeting Neuroinflammation Directly - We could explore new anti-inflammatory compounds, immunomodulators, or even cell therapies designed to rebalance the brain's immune environment. Rewriting the Code with Gene Editing - Imagine using in vivo base or prime editing to convert APOE4 to APOE2. Given APOE2's protective qualities, this could fundamentally alter an individual's inflammatory landscape. The Power of Patient Stratification This new understanding also makes me curious about existing data. Take the recent Nature study that explored the effects of herpes zoster vaccination on dementia risk (https://lnkd.in/eru_KvgR). It would be incredibly insightful to re-examine those findings, specifically stratifying participants by their APOE4 carrier status. Could this reveal how genetics influence the impact of environmental factors like vaccination and infection on brain health? The convergence of these scientific insights presents a compelling, still-developing narrative for the neurodegenerative field. It challenges us to explore new avenues: from targeting inflammation and exploring gene editing, to leveraging genetic insights for more precise patient stratification. While we're not at definitive answers, this new line of inquiry into APOE4 and its inflammatory signature offers a fresh, thought-provoking direction. It certainly makes me curious to explore more. Pretty cool!

🔍 New Review Alert | Journal of Integrative Neuroscience, 24(4) “Inhibition of Neutrophil Extracellular Traps: A Potential Therapeutic Strategy for Hemorrhagic Stroke” Critically evaluates how NET-driven neuroinflammation and micro-thrombosis exacerbate secondary brain injury after hemorrhagic stroke. Key insights • Pathobiology: NETosis—via both NOX-dependent & NOX-independent pathways—compromises the BBB, fuels cytokine cascades and fosters early micro-clot formation. • Therapeutic targets: PAD4 inhibitors (GSK484, Cl-amidine), DNase I–mediated NET dismantling, TREM-1 blockade and neutrophil-targeted nanoparticles show pre-clinical promise. • Translational outlook: Selective NET inhibition could complement conventional stroke care, paving the way for precision immunotherapy in neurovascular medicine. Open-access article ▶︎ https://lnkd.in/dknCpEjX #Neuroimmunology #StrokeResearch #NETosis #Neuroscience

🧠 Advancing Alzheimer's Treatment: A Breakthrough in Mesenchymal Stem Cell Therapy 🧫 🔬 A Phase 2a clinical trial in Nature Medicine highlights laromestrocel (Lomecel-B), an allogeneic mesenchymal stem cell (MSC) therapy, as a safe and potentially disease-modifying treatment for mild Alzheimer’s disease (AD). 🔬 Key Findings 🔷 Safe & Well-Tolerated ◾ No infusion-related reactions, hypersensitivities, or amyloid-related imaging abnormalities (ARIA). ◾ Serious adverse events (SAEs) were low and comparable across groups, even in ApoE4 carriers. 🔷 Slowing Brain Atrophy & Neuroinflammation ✔️ Whole-brain atrophy slowed by 48.4% (P = 0.005), hippocampal atrophy by 61.9% (P = 0.021). ✔️ Reduced neuroinflammation, as measured by diffusion tensor imaging (DTI) in the cingulate cortex (P = 0.048). 🔷 Cognitive & Functional Improvements ◾ Montreal Cognitive Assessment (MoCA): Significant improvement (P = 0.009). ◾ Mini-Mental State Exam-2 (MMSE-2): Brain volume preservation correlated with cognitive stability (R = 0.41, P = 0.0075). ◾ Daily Living Activities (ADCS-ADL): Higher scores in high-dose group (P = 0.040), indicating better function. 🔷 Beyond Amyloid: A Novel Approach ◾ Unlike anti-amyloid monoclonal antibodies, laromestrocel targets neurovascular integrity and inflammation, avoiding ARIA risks. ◾ Blood biomarkers confirmed vascular protection, reducing soluble TIE2 (sTIE2), a key marker of blood-brain barrier health. ◾ Ventricular enlargement, a hallmark of disease progression, was significantly reduced. 🔜 What’s Next? With a safety profile and early efficacy signals, MSC-based therapies could reshape Alzheimer’s treatment. Larger trials are needed to confirm long-term benefits. #StemCellTherapy #Neuroscience #ClinicalTrials #Biotech #Innovation

Scientists Use SynNotch Technology to Transform T Cells to Treat Neurological Diseases Scientists published an important study in the journal Science, using synNotch technology to transform T cells and explore its potential in treating neurological diseases. The difficulty in treating central nervous system (CNS) diseases lies in the existence of the blood-brain barrier, which many drugs cannot penetrate, while T cells have the ability to freely cross the blood-brain barrier. The research team designed synNotch receptors for T cells to target brain cells, and achieved flexible treatment for brain cell lesions by adjusting the drug payload. This treatment model can be used for precise targeting of primary and secondary brain cancers, and can also improve the condition of neuroinflammatory-related diseases. The synNotch technology was first proposed in 2016 to solve the problem of single target recognition of traditional CAR-T or TCR-T. By introducing a Notch receptor, the modified T cells add a layer of insurance mechanism for precise recognition, thereby improving the accuracy of immune recognition and the safety of treatment. The research team screened a group of CNS-specific extracellular ligands through a public database and finally locked in the brevican (BCAN) protein as a target. This is an extracellular matrix component unique to the brain. In the experiment, the researchers combined anti-BCAN synNotch with anti-EphA2/IL13Rα2 CAR-T to treat mouse models of glioblastoma and breast cancer brain metastasis, respectively, and achieved significant therapeutic effects without affecting other tissues outside the brain. When the drug carrier was replaced with interleukin-10 (IL-10), this technology showed significant improvement in neuroinflammation in mice with experimental autoimmune encephalomyelitis. In addition, the researchers also believe that this technology combination may be used in the treatment of neurodegenerative diseases in the future, showing great clinical potential. Reference [1] Miloss Simic et al., Science 2024 (DOI: 10.1126/science.adl4237) #CNSImmunotherapy #synNotch #TCellTherapy #Glioblastoma #BrainHealth #Neuroinflammation #CAR_TCells #PrecisionMedicine #ScienceInnovation

Blood-brain-immune interface and neurodegenerative disorders The lab have long investigated how blood that leaks into the brain trigger neurologic diseases, essentially by hijacking the brain’s immune system and setting off a cascade of harmful often-irreversible effects that result in damaged neurons. One blood protein in particular—fibrin, normally involved in blood coagulation—is responsible for setting off this detrimental cascade. The process has been observed in conditions as diverse as Alzheimer’s, traumatic brain injury, multiple sclerosis, premature birth, and even COVID-19. However, the team found that the process could be prevented or interrupted by “neutralizing” fibrin to deactivate its toxic properties—an approach that appears to protect against many neurological diseases when tested in animal models. The scientists previously developed a drug, a therapeutic monoclonal antibody, that specifically targets fibrin’s inflammatory properties without affecting its essential role in blood coagulation. This fibrin-targeting immunotherapy has shown, in mice, to protect from multiple sclerosis and Alzheimer’s, and to treat neurological effects of COVID-19. A humanized version of this first-in-class fibrin immunotherapy is already in Phase 1 safety clinical trials by Therini Bio, a biotech company launched to advance discoveries from the lab. #ScienceMission #sciencenewshighlights https://lnkd.in/gN8PqweG

Inflammation plays a big role in many underlying diseases that we’re now just starting to recognize and investigate. In particular, neuroinflammation holds much potential (e.g. MS, AD, psychiatry, oncology, etc) and biopharma interest in this area is heating up. I remember talking a good friend of mine (who’s an MD) saying #psychedelics can reduce TNF-alpha (tumor necrosis factor), a proinflammatory biomarker. He was befuddled as this has been demonstrated in multiple rodent species and humans. As can be inferred by the name, it’s a biomarker linked to tumors / cancer so why do psychedelics play a role here? It’s currently unclear but this, and other anti-inflammatory targets, represent an important and tangible liquid biomarker that can easily be assessed clinically. Biomarkers like this are sorely missing in many CNS disorders which can limit animal to human translation and clinical viability. It’s an understatement to say the anti-inflammatory activity of psychedelics are often overlooked. For example, R-DOI has picomolar (pM!) activity to inhibit IL-6. Reductions in IL-6 are also correlated to the duration of positive mood effects, a known psychedelic benefit, in humans. More interestingly, the anti-inflammatory effects of R-DOI are well below the psychedelic dosing threshold... In another study, rodents given a high fat diet and R-DOI had significantly less cholesterol levels than control. The cholesterol levels were highly correlative to reductions in TNF-alpha, IL-6, and VCAM-1. While it’s unlikely that psychedelics will supplant #GLP-1 agonists, it’s known that 5-HT2C agonists (a conserved target across most psychedelics) have led to the approval of weight loss drugs, i.e. lorcaserin. With regards to neurodegeneration, inflammation is highly correlated to tau and beta-amyloid (AB) pathologies. Increased #astrocyte and #microglial activities upregulate proinflammatory markers (e.g. TNF-alpha, IL-1, and IL-6) which are prominent features of most AD patients. The current AB drugs remove these plaques but also increase brain swelling in a significant portion of patients with limited benefits on cognition. In my opinion, a major reason hindering broad psychedelic acceptance within #biopharma and the medical community is the psychedelic side effects. This anti-inflammatory angle certainly adds more credibility to a next-generation approach and is well within the scope of many high value pharmaceutical programs. Many preclinical investigations are underway and clinical trials of psychedelics are assessing these anti-inflammatory biomarkers. This is an area to watch closely as these biomarkers de-risk clinical development and will provide insight into non-hallucinogenic or sub-hallucinogenic treatments. Scientific and clinical validation can be a long road, but can we get there without the trip? #sciencesunday

Rethinking Alzheimer’s Disease: From Plaques to the Inflammasome A growing body of evidence is reshaping how we understand Alzheimer’s disease (AD). Beyond amyloid plaques and tau tangles, research is now spotlighting the innate immune system, specifically the NLRP3 inflammasome, as a critical driver of neurodegeneration. A new study in the Journal of Alzheimer’s Disease characterizes AD as an autoinflammatory immune pathology, highlighting: Activation of the NLRP3 inflammasome in response to amyloid-β and phosphorylated tau Upregulation of proinflammatory cytokines and immune-related secretomes Evidence for trained immunity and even cell trans-differentiation, where brain cells adopt inflammatory immune phenotypes At Halia Therapeutics, we’re pioneering treatments that directly target these underlying inflammatory pathways. Our lead candidate, HT-4253, is an oral LRRK2 inhibitor designed to suppress neuroinflammation in APOE4 homozygous individuals—those at highest genetic risk for AD. Inflammation is not just a symptom of Alzheimer’s—it may be the starting point. It’s time to rethink how we treat neurodegeneration. If we can intercept the cycle of inflammation and immune dysfunction early, we may not only slow progression but also prevent disease onset. Let’s move beyond plaque and start targeting what’s upstream! https://lnkd.in/gXkK6_pi #AlzheimersDisease #Neuroinflammation #Inflammasome #TrainedImmunity #HaliaTherapeutics #Neuroscience #PrecisionMedicine #Biotech