Neurofilament light as a biomarker

Can you tell us about your origin and the current role?

My name is Phillip Mitchell, I am currently the scientific director at the Charles River Laboratories. I have experience in biochemistry and doctorate. In molecular biology. My career lasts over 30 years in the field of discovering medicines, including a role in the academic environment, biotechnology, pharmaceutical environment, and recently in the research organization sector.

What are some of the key challenges and the latest progress in discovering drugs in biomarkers for the central nervous system (CNS)?

CNS diseases represent a growing global health burden, partly attributed to the aging population. However, even with better understanding of the mechanisms of the disease, the high indicator of failure persists in discovering neuronouka drugs, often because of the challenges of effectiveness. In addition, many clinical trials are based on subjective measurements of clinicists’ assessment as primary end points, which can be time consuming and prone to variability.

In recent years, neuroimaging biomarkers, such as positron emission ligands (PET), have significantly contributed to the clinical stages of CNS drug development by helping in determining the dose in the examination of drugs focused on new mechanisms. Also, the discovery of less invasive biomarkers based on fluid, especially in cerebrospinal fluid (CSF) and blood, played a key role in the development of CNS biomarkers research, although significant challenges remains.

One of the visible examples is the light of neurofilament (NFL), structural protein found only in neurons. The NFL plays a key role in the stability of neuronal structures, especially in large, myelined axons, which are based on NFL for radial growth. The low level of NFL is released continuously under normal conditions, but there may be a significant increase in response to axon damage as a result of inflammatory, neurodegenerative, traumatic or vascular events. Given its stability and abundance, NFL is a valuable biomarker to assess CNS health.

How was NFL measurement, pre -clinical and clinical stages of drug discovery and development?

NFL has extensive use as a biomarker at various stages of CNS research, from pre -clinical tests to clinical trials. The research used the NFL to measure inflammatory toxicity intermediary by microglej in response to, for example, antishane oligonucleotides. Similarly, pre -clinical models have shown that NFL levels in plasma and CSF may indicate axonal health and the progression of the disease in neurodegenerative diseases and neurine.

NFL levels are a substitute biomarker in clinical conditions used to monitor CNS health, tracking neurodegenerative susceptibility to diseases and assessing the effectiveness of treatment. The consistent sensitivity of NFL at these stages makes it invaluable to monitor axon degeneration and the risk assessment of neurotoxicity, emphasizing its key role in therapeutic development and patient safety.

How does NFL work as a biomarker of neurodegeneration and CNS damage?

High NFL levels in CSF indicate a leakage of damaged or degenerating neurons, and studies have shown that the increased CSF NFL strongly correlates with CNS damage. For example, a 2006 study on amateur boxers showed a significant increase in CSF NFL after seizures, and the levels dropped after rest. In addition, higher output NFL levels were associated in extended severity of injuries and faster disease progress in states such as amiotrophic lateral sclerosis (ALS).

Numerous studies have shown a strong correlation between NFL levels in plasma and CSF, which suggests that plasma measurements can effectively reflect the ongoing CNS damage. However, because NFL levels in plasma are usually lower than in CSF, ultra -sensitive tests are necessary for accurate quantification.

In the context of neurodegenerative diseases, such as Huntington’s disease and Alzheimer’s (AD) disease, increased NFL levels in patient plasma and CSF serve as valuable diagnostic and prognostic indicators, correlating with disease progression and helping to distinguish between different levels of damage.

How is NFL used in AD research and what insights does the risk of dementia provide?

Increased NFL levels are usually observed in patients with AD, compared to mild cognitive disorders or healthy controls. However, NFL levels in plasma increase with age even in healthy populations, so these measurements must take care of age. In the case of use with other biomarkers, such as Amyloid-Beta 42, NFL promises that it identifies people with a higher risk of developing dementia.

This combined biomarker approach can improve the choice of patients in Alzheimer’s clinical trials. Recent studies have shown reference levels of NFL in plasma in different centuries, contributing to the integration of NFL measurements to diagnostic and disease monitoring in neuropsychiatric and neurodegenerative conditions.

How can NFL levels indicate treatment response in neurodegenerative diseases, such as spinal muscles?

NFL levels proved to be valuable to monitor the response to treatment in the muscles of the spine, which causes degeneration of the motor neuron. For example, in infants and children treated with anti -spy oligonucleotide nusinersen NFL levels in CSF were normalized after treatment, which coincides with a significant improvement in motor function. This fast decrease in NFL levels suggests that NFL can serve as an early response marker, helping doctors assessing the effectiveness of treatment and management of therapeutic decisions.

Similarly, the last study of patients from ALS treated with tofofersen showed a significant reduction in plasma NFL levels, despite the fact that the basic clinical end points of treatment were unsatisfied. The FDA granted approval on the basis of these changes in biomarkers, emphasizing the role of NFL as a marker of answers for the treatment of neurodegenerative disease.

What is the importance of NFL as a safety biomarker for detecting neurotoxicity induced with a drug?

NFL levels offer a non -invasive, sensitive approach to detecting neurotoxicity, which is crucial for assessing the safety of certain treatments, such as chemotherapy, known for causing peripheral neuropathy. Studies have shown that changes in serum NFL levels can predict a later start and intensification of peripheral neuropathy, enabling clinicians to balance the effectiveness of treatment with patient safety.

The role of NFL as a marker of neurotoxicity also translated into pre -clinical settings. For example, in phase 2b for Huntington’s disease involving Branaplam, some patients have developed peripheral neuropathy. Control tests showed increased NFL levels in Branaplam animals despite the lack of neurological symptoms, strengthening the utility of NFL as a pre -clinical safety biomarker.

How does artificial intelligence (AI) currently affect biomarker selection strategies?

AI significantly increases the discovery of biomarkers by rapid analysis of large databases, including proteomics, metabolomics and transcriptomics. AI improves data extraction and helps to identify new biomarkers and therapeutic goals by analyzing the risk factors.

In Charles River Laboratories we have recently established cooperation with Aitia, a company specializing in biomarkers under AI control. This cooperation uses the heterophylling models from cancer to create “digital twins”, which simulate patients ‘answers, offering a precise, effective approach to biomarkers’ selection in discovering drugs.

About Phillip Mitchell

Phil Mitchell has a doctorate in the biology of molecular cells (cancer) from the Institute of Cancer Research and bachelor from Biochemistry from the University of Liverpool. Currently, he is the scientific director of integrated biology at the Charles River Laboratories, where he has been conducting pre -clinical efforts to discover drugs for over eight years, specializing in the development of in vitro testing and pharmacology.

About Charles River Laboratories

On Charles RiverWe are passionate about our role in improving the quality of life of people. Our dedicated team of pre -clinical scientists in neurobiology wants the same as you: Find a cure for destructive diseases of the central nervous system. From basic research to regulatory approval, we have a leading study, scope of services and an approach to cooperation that you need to discover and develop new therapies.

We understand the challenges and complexity in search of potential therapy of neurological disorders. The combination of our comprehensive services for discovering neuroscience and specialist knowledge supports the creation of configurable, innovative and efficient solutions for your research. Our team of neuronauków still establishes the most appropriate and models as well as tests of acute and chronic neurological diseases to help our partners identify and test new relationships in this difficult field.