CDP-19: [Funding] Galectin-3 Inhibitors in CNS Proof of Concept study

One liner: The Galectin-3 Inhibitors project is testing the concept of treating neuroinflammation through a small molecule known to inhibit Galectin-3 in peripheral indications, via direct injection to the brain in the mouse model of Alzheimer’s disease. Galectin-3 is involved in neuroinflammation, thereby the project has a potential to be used in multiple neurodegenerative diseases.

Cerebrum DAO Deal Team

• Senior reviewers: Brett Abrahams (Neuroscience), Peter Groenen (Translational Science), Klaus Beck (Translational Science)
• Project Team: Peter Groenen, Maryna Polyakova, Michele Gallia
• Sourced by: Michele Gallia

Project Team

• Principal Investigator: Prof. Tomas Deierbrog, PhD
• Translational Neuroscience Advisor: Brett Abrahams, PhD
• Medicinal Chemistry Advisor: Prof. Ulf Nilsson
• Project Team: Maryna Polyakova, PhD

Summary Deal Analysis

Tomas Deierborg and colleagues have presented convincing data on the specific involvement of Galectin 3 (Gal-3, encoded by LGALS3) in neuroinflammatory processes, particularly in Alzheimer's Dementia (AD). Gal-3 is a β-galactoside-binding protein encoded by the LGALS3 gene, playing roles in cell adhesion, immune responses, and inflammation. It is expressed in various cellular compartments and secreted into extracellular spaces, influencing processes like microglial activation and amyloid-β (Aβ) aggregation [1].

The group of Deierborg, has extensively studied the biological effects of Gal-3 in neuroinflammation and neurodegeneration. They have shown that Gal-3 is upregulated in microglia surrounding Aβ plaques and tau aggregates in AD patients and mouse models. It binds to receptors like TREM2 and TLR4, amplifying proinflammatory pathways that drive neurodegenerative processes[1, 2]. Gal-3 promotes Aβ aggregation and plaque persistence. It interacts with hyperphosphorylated tau (pTau), worsening neuronal uptake and synaptic loss [3]. Currently no small molecule Gal-3 inhibitors that pass the BBB exist. Tomas Deierborg and colleagues have access to a small molecule Gal-3 inhibitor that is soluble and binds Gal3 in the periphery, but not in the brain (GB1265). The group also has a small molecule that passes the BBB but reveals low affinity for Gal-3.

In the current in vivo study the direct inhibition of the Gal-3 delivered directly into the brain via a micropump (Alzeth pump) is proposed. This study will evaluate potential therapeutic effects of a future brain-penetrant molecule. The outcome of this proof-of-principle study will provide the data for the go-no-go decision in the discovery of brain-penetrant small molecules. More specifically, the GB1265 will be delivered through intraventricular injections in FAD mice for 4 weeks. The study outcomes will include biomarkers of Neuroinflammation and Amyloid pathology in the brain.

Problem

Neuroinflammation is a key pathological mechanism in the majority of neurodegenerative diseases. Current research indicates that sustained neuroinflammation is a driver of AD pathology along with amyloid and tau accumulation. With the limited clinical benefit by the currently approved treatments against amyloid pathology, a wider interest has emerged to treat the neuroinflammatory component. While a number of approved anti-inflammatory drugs treat diseases like multiple sclerosis (MS) there are currently no approved anti-inflammatory drugs for neuroinflammation that have reached market approval stage. A limiting factor for effective anti-inflammatory therapeutics is the blood-brain barrier (BBB). While Galectin 3 is recognized as a key mediator, currently available inhibitors show low brain exposure, limiting the testing of the therapeutic benefit.

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Please visit the following link to view the full proposal, as the proposal content exceeds Snapshot's character limit: https://docs.google.com/document/d/1QQAfZD7T_-P-KPDQfa4EaQuLTe3EGtpmAQIp3ryPWqU/edit?usp=sharing