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Neuro-Immunology: The Promise Of A Differentiated Approach To Neurodegenerative Disease – LifeSciVC

By Ivana Magovčević-Liebisch, CEO of Vigil Neuroscience, as part of the From The Trenches feature of LifeSciVC

In the last decade, our industry has made great strides in combating cancer by harnessing the body’s own immune system. As it was recently pointed out in From The Trenches, anti-PD-1 agents were part of a fundamental shift in the oncology landscape, offering patients a new treatment option that would transform the way we approach cancer and the value proposition for companies.

Building upon the learnings of the immuno-oncology space, we have also come to appreciate that the brain’s immune system offers the same promising pathway for treating neurodegenerative disease. Neuroimmunology examines the connection between the central nervous system (CNS) and the immune system to understand inflammatory mechanisms that contribute to the progression of neurological diseases. At Vigil, we believe neuroimmunology is the next frontier in medicine.

An enhanced understanding of the role of the immune system in modulating neurodegeneration and advancements in individualized medicine have enabled a new frontier in drug development for the treatment of rare and common neurodegenerative diseases.

The Magic of Microglia  

Microglia are the brain’s immune cells, and they play a key role in our brain’s damage response. Serving as sentinel immune cells of the CNS, microglia perform a critical role in maintaining its health by continuously sensing and responding to multiple types of signals, including those caused by disease. Think of microglia as the brain’s cleanup crew: they identify problem areas, tag debris for removal, and initiate a defense response.

Microglial dysfunction has been linked to both rare and common neurodegenerative diseases. These diseases include leukoencephalopathies and leukodystrophies that are associated with genetic mutations or variations, such as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and Alzheimer’s disease (AD). At Vigil, these discoveries led us to focus on microglia and microglia-targeted therapeutics.

More specifically, our clinical programs are focused on triggering receptors expressed on myeloid cells 2 [TREM2], a receptor found on microglia. Functional TREM2 is required, not only for microglial maintenance functions, but also for responses to CNS damage, decay, and debris that occurs in both natural and disease states.

Targeting TREM2

TREM2 is a receptor that sits on microglia and acts as a key environmental sensor in the brain. It is the first compelling and tractable molecular target for modulating microglial biology.

When TREM2 is activated, it converts microglia from their homeostatic state to an active, neuroprotective state. When there’s a loss of function of TREM2, the microglia are compromised and unable to respond to the normal binding partners that signal conversion into this neuroprotective state, leading to the accumulation of debris and ultimately to neurodegeneration. Because microglia are responsible for a broad range of activities, microglial dysfunction is associated with several rare and common neurological diseases.

Start Small to Win Big

At Vigil, our precision medicine strategy focuses on indications with strong genetic, mechanistic, and biochemical associations with microglial deficiency. We believe this strategy reduces the downstream translational risk and allows us to gather proof of concept more quickly. This strategy also led us to our first indication: ALSP, a rare genetic disease in at least 10K individuals just in the U.S.

ALSP is caused by a mutation of the CSF1R gene which results in the malfunction of microglia. This malfunction causes cells to lose their ability to protect the brain, leading to the onset of disease symptoms which worsen aggressively over time. The average age of onset for ALSP is mid-40s and its rapid progression leaves patients incapacitated in 3-4 years with an average mortality of 6-7 years.

Given that ALSP is autosomal dominant, which means that individuals with a mutated CSF1R gene have a 50% chance of passing the disease on to their children, the disease has devastating effects on families across multiple generations simultaneously. When we speak to clinicians in this area, they don’t refer to individual patients, but the ravaging of entire families.

There are no treatments that slow the progression of the disease, and existing care and management practices only focus on symptom relief with limited benefit to the patients’ quality of life.

I was fortunate to have the privilege of starting my career in life sciences in the rare disease space, which has allowed me to understand what it means to help those with no treatment options currently available. I have seen firsthand the devastating impacts of rare diseases on patients, their families and their communities. Too many of these patients must face their diagnosis without the hope of medical interventions to slow progression, lessen symptoms or cure the disease.

The Path Forward

Recent advancements in neuro-immunology have allowed us to better understand the connection between TREM2 and CSF1R. Through the activation of microglia, we are enabling the patient’s own immune system to fight this debilitating disease.

For ALSP we are evaluating iluzanebart, our monoclonal antibody TREM2 agonist which is currently in a Phase 2 study. We plan to expand into other rare microgliopathies using our precision medicine strategy: focusing on genetically defined leukodystrophies where the blood-brain barrier is compromised, positioning them well for antibody therapies.

Our second clinical candidate is a small molecule that is being evaluated for the treatment of Alzheimer’s disease, a common neurodegenerative disease that can also be associated with microglial dysfunction.

Neuroimmunology holds tremendous promise for patients and caregivers that are living with the realities of these progressive, and often debilitating conditions. As our knowledge of these mechanisms of action increases, so too should our investment in and exploration of potential treatment options.