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Identifying brain-penetrant small-molecule modulators of human microglia using a cellular model of synaptic pruning
Liam T McCrea1, Rebecca E Batorsky2, Joshua J Bowen1
1Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
Abstract:
Microglia dysregulation is implicated across a range of neurodevelopmental and neurodegenerative disorders, making their modulation a promising therapeutic target. Using PBMC-derived induced microglia-like cells (piMGLCs) in a scalable assay, we screened 489 CNS-penetrant compounds for modulation of microglial phagocytosis of human synaptosomes in a validated assay for microglia-mediated synaptic pruning. Compounds from the library that reduced phagocytosis by ≥2 standard deviations across the library without cytotoxicity were validated in secondary screens, with 28 of them further confirmed to reduce phagocytosis by 50% or more. These compounds comprise a wide range of therapeutic classes with different mechanisms of action, including immunosuppressants, kinase inhibitors, antipsychotics, and epigenetic modulators. Image-based morphological measurements were calculated to measure the degree of ramified vs. ameboid morphotypes as an indicator of activation state. Additionally, transcriptomic profiling indicated divergent effects on cell signaling, metabolism, activation, and actin dynamics across confirmed compounds. In particular, multiple CNS-penetrant small molecules with prior FDA approval or demonstration of safety in vivo demonstrated modulatory effects on microglia. For example, identified drugs such as the tyrosine kinase inhibitors lapatinib, alectinib, and lazertinib and the epigenetic modulator vorinostat have been approved for various cancer treatments and are being investigated for other indications; however, they have not been extensively studied in patients for neurodevelopmental and neurodegenerative disorders. These potential disease-modifying agents represent high-priority candidates for repositioning studies in neurodevelopmental, neuroinflammatory, or neurodegenerative disorders.
Insights
Researchers screened 489 CNS-penetrant compounds to identify drugs that modulate microglial phagocytosis. They found 28 compounds, including approved cancer drugs, that significantly reduce microglial activity, offering potential for neurodegenerative disease therapies.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Microglia dysregulation is linked to neurodevelopmental and neurodegenerative disorders.
- Modulating microglial function presents a promising therapeutic avenue.
Purpose of the Study:
- To screen a library of CNS-penetrant compounds for their ability to modulate microglial phagocytosis.
- To identify potential therapeutic agents for neurodevelopmental, neuroinflammatory, and neurodegenerative disorders.
Main Methods:
- Utilized PBMC-derived induced microglia-like cells (piMGLCs) in a scalable assay.
- Screened 489 CNS-penetrant compounds for modulation of microglial phagocytosis of human synaptosomes.
- Validated compounds through secondary screens, morphological analysis, and transcriptomic profiling.
Main Results:
- Identified 28 compounds that significantly reduced microglial phagocytosis (≥50%) without cytotoxicity.
- Confirmed compounds represent diverse therapeutic classes, including kinase inhibitors and epigenetic modulators.
- Observed divergent effects on cell signaling, metabolism, and actin dynamics.
Conclusions:
- Multiple CNS-penetrant small molecules, including FDA-approved drugs like lapatinib and vorinostat, show potential for repositioning in neurological disorders.
- These identified compounds are high-priority candidates for further investigation in neurodevelopmental, neuroinflammatory, and neurodegenerative diseases.
