STUDY: Rescue of in vitro models of CSF1R-related adult-onset leukodystrophy by iluzanebart: mechanisms and therapeutic implications of TREM2 agonism

February 19, 2025

Understanding CSF1R-Related Leukodystrophy and a Potential New Treatment: Iluzanebart

This study titled Rescue of in vitro models of CSF1R-related adult-onset leukodystrophy by iluzanebart: mechanisms and therapeutic implications of TREM2 agonism and published by Journal of Neuroinflammation, explores CSF1R-related adult-onset leukodystrophy with axonal spheroids and pigmented glia (CSF1R-ALSP), a rare neurodegenerative disease caused by mutations in the CSF1R gene. This condition leads to the loss of microglial function, which affects brain health and causes progressive neurological symptoms in adulthood, typically around the fourth decade of life. Currently, there are no approved treatments for CSF1R-ALSP, and many patients are initially misdiagnosed with more common conditions like Alzheimer’s disease or multiple sclerosis.

What Does the CSF1R Gene Do?

The CSF1R gene provides instructions for producing a receptor that is essential for the growth, survival, and function of microglia—the immune cells of the brain. These cells play a key role in clearing waste, maintaining nerve function, and protecting the brain from damage. When the CSF1R gene is mutated, microglia do not work properly or die, leading to brain tissue damage, loss of white matter (myelin), and neurological decline.

A New Approach: Targeting the TREM2 Gene

Researchers have found that another gene, TREM2, has a similar function to CSF1R in microglia. Activating TREM2 could potentially compensate for the loss of CSF1R function and restore microglial activity.

The study focuses on a new experimental drug called Iluzanebart, a monoclonal antibody designed to activate TREM2 and restore microglial function. The researchers tested Iluzanebart on human cells and mouse models to see if it could help microglia survive, function better, and reduce brain damage.

Key Findings of the Study

1. Iluzanebart Effectively Activates TREM2 in Human Cells

  • Iluzanebart was tested on different human cell models, including:
    • Genetically modified cells expressing TREM2
    • Macrophages (a type of immune cell)
    • Induced pluripotent stem cell-derived microglia (iMGL), which closely resemble brain microglia
  • The drug strongly activated TREM2 in these cells, increasing phosphorylation of key proteins involved in microglial function.

2. Iluzanebart Rescues Microglia Function in Models of CSF1R-ALSP

  • In disease models where CSF1R function was artificially blocked, microglia became less viable and more prone to cell death.
  • Treatment with Iluzanebart rescued these microglia, making them:
    • More resistant to cell death
    • More active and functional
    • Better able to maintain their normal shape and role in the brain

3. Iluzanebart Restores CSF1R Activity in Mutant Microglia

  • The study created a lab-grown model of CSF1R-ALSP using CRISPR gene editing to introduce the I794T mutation, the most common CSF1R mutation found in patients.
  • In these mutant microglia, Iluzanebart:
    • Increased survival and function
    • Restored CSF1R signaling to normal levels
    • Boosted microglial activity, similar to healthy cells

4. Iluzanebart Shows Positive Effects in Mice with Human TREM2

  • Mice engineered to express human TREM2 were given Iluzanebart, which:
    • Activated microglia in the brain
    • Increased expression of key immune and anti-inflammatory genes
    • Improved microglial survival and function
    • Raised CSF1R levels, suggesting enhanced brain immune activity

5. Iluzanebart Induces Protective Brain Changes

  • Brain samples from treated mice showed higher levels of key proteins involved in brain repair, including:
    • IP10 (CXCL10), MIP1α (CCL3), and MCP1 (CCL2)—chemicals that help regulate brain immune responses.
  • These changes suggest that Iluzanebart promotes microglial health and function in living organisms.

What This Means for Patients

These findings suggest that Iluzanebart could be a promising treatment for CSF1R-ALSP by:

  1. Compensating for defective CSF1R signaling through TREM2 activation.
  2. Restoring microglial survival and function, potentially slowing disease progression.
  3. Increasing brain immune responses that could help prevent further damage.

If successful in future clinical trials, Iluzanebart could be the first targeted treatment for CSF1R-ALSP, offering hope for patients who currently have no effective treatment options.

Next Steps

  • Iluzanebart has already been tested for safety in healthy volunteers.
  • A Phase 2 clinical trial (IGNITE, NCT05677659) is currently testing its effectiveness in patients with CSF1R-ALSP.
  • If these trials confirm its benefits, Iluzanebart could become an approved therapy, potentially transforming how CSF1R-ALSP is treated.

Conclusion

This study provides strong evidence that activating TREM2 with Iluzanebart can restore microglial function and compensate for CSF1R loss. While further testing is needed, these findings represent a major breakthrough in the search for treatments for CSF1R-ALSP.

For more details, the full article can be accessed here.

*The United Leukodystrophy Foundation is not liable for any inaccuracies or gaps in these overviews , which are offered “as is” without assurances on completeness, accuracy, or timeliness. For verification or detailed information, please consult the original articles directly.
As a leukodystrophy related nonprofit, the ULF provides awareness to scientific literature. Inclusion on our website does not imply endorsement of, or agreement with, the contents by the ULF.